Heterocyclic compounds

ABSTRACT

The present invention relates to compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to heterocyclic compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with enzymes having histone deacetylase (HDAC) activities.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Phase filing under 35 U.S.C. §371 ofPCT/SG2006/000217 filed Aug. 1, 2006, which claims priority toProvisional Patent Application No. 60/714,827, filed in the UnitedStates on Sep. 8, 2005, and Provisional Patent Application No.60/783,819, filed in the United States on Mar. 21, 2006. The entirecontents of each of the above-applications is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to hydroxamate compounds that areinhibitors of histone deacetylase (HDAC). More particularly, the presentinvention relates to heterocyclic compounds and methods for theirpreparation. These compounds may be useful as medicaments for thetreatment of proliferative disorders as well as other diseasesinvolving, relating to or associated with enzymes having histonedeacetylase (HDAC) activities.

BACKGROUND OF THE INVENTION

Local chromatin architecture is generally recognized as an importantfactor in the regulation of gene expression. The architecture ofchromatin, a protein-DNA complex, is strongly influenced bypost-translational modifications of the histones which are the proteincomponents. Reversible acetylation of histones is a key component in theregulation of gene expression by altering the accessibility oftranscription factors to DNA. In general, increased levels of histoneacetylation are associated with increased transcriptional activity,whereas decreased levels of acetylation are associated with repressionof gene expression [Wadem P. A. Hum. Mol. Genet. 10, 693-698 (2001), DeRuijter A. J. M. et al, Biochem. J., 370, 737-749 (2003)]. In normalcells, histone deacetylases (HDACs) and histone acetyltransferasetogether control the level of acetylation of histones to maintain abalance. Inhibition of HDACs results in the accumulation of acetylatedhistones, which results in a variety of cell type dependent cellularresponses, such as apoptosis, necrosis, differentiation, cell survival,inhibition of proliferation and cytostasis.

Inhibitors of HDAC have been studied for their therapeutic effects oncancer cells. For example, suberoylanilide hydroxamic acid (SAHA) is apotent inducer of differentiation and/or apoptosis in murineerythroleukemia, bladder, and myeloma cell lines [Richon V. M. et al,Proc. Natl. Acad. Sci. USA, 93: 5705-5708 (1996), Richon V. M. et al,Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998)]. SAHA has been shownto suppress the growth of prostate cancer cells in vitro and in vivo[Butler L. M. et al, Cancer Res. 60, 5165-5170 (2000)]. Other inhibitorsof HDAC that have been widely studied for their anti-cancer activitiesare trichostatin A (TSA) and trapoxin B [Yoshida M. et al, J. Biol.Chem., 265, 17174 (1990), Kijima M. et al, J. Biol. Chem., 268, 22429(1993)]. Trichostatin A is a reversible inhibitor of mammalian HDAC.Trapoxin B is a cyclic tetrapeptide, which is an irreversible inhibitorof mammalian HDAC. However, due to the in vivo instability of thesecompounds they are less desirable as anti-cancer drugs. Recently, othersmall molecule HDAC inhibitors have become available for clinicalevaluation [U.S. Pat. No. 6,552,065]. Additional HDAC inhibitingcompounds have been reported in the literature [Bouchain G. et al, J.Med. Chem., 46, 820-830 (2003)] and patents [WO 03/066579A2]. The invivo activity of such inhibitors can be directly monitored by theirability to increase the amount of acetylated histones in the biologicalsample. HDAC inhibitors have been reported to interfere withneurodegenerative processes, for instance, HDAC inhibitors arrestpolyglutamine-dependent neurodegeneration [Nature, 413(6857): 739-43, 18Oct. 2001]. In addition, HDAC inhibitors have also been known to inhibitproduction of cytokines such as TNF, IFN, IL-1 which are known to beimplicated in inflammatory diseases and/or immune system disorders. [J.Biol. Chem. 1990; 265(18): 10232-10237; Science, 1998; 281: 1001-1005;Dinarello C. A. and Moldawer L. L. Proinflammatory and anti-inflammatorycytokines in rheumatoid arthritis, A primer for clinicians, 3^(rd)Edition, Amgen Inc., 2002].

Nevertheless, there is still a need to provide further HDAC inhibitorsthat would be expected to have useful, improved pharmaceuticalproperties in the treatment of diseases such as cancer,neurodegenerative diseases, disorders involving angiogenesis andinflammatory and/or immune system disorders. With a view to meeting thisneed a number of small organic moiety scaffolds have been investigatedincluding a number of heterocyclic systems, especially bicyclicheterocyclic ring systems. One heterocyclic system that has beeninvestigated has been the benzimidazole ring system. We have now foundthat judicious selection of the substituents on the 5 membered ring ofthe benzimidazole ring system leads to the production of a family ofcompounds with improved pharmacokinetic properties when compared withthe compounds of the prior art. The compounds within the family exhibitmicrosomal stability and thereby demonstrate improved half lives in theplasma when compared to the compounds of the prior art. The compoundswithin the family typically provide a longer duration of action due tothe increased in vivo exposure (i.e., area under the curve,AUC_(0-last)) thereby yielding improved tumor growth inhibition profilesin the xenograft models.

SUMMARY OF THE INVENTION

In one aspect the present invention provides a compound of the formula(I):

wherein

R¹ is an optionally substituted heteroaryl group, an optionallysubstituted heterocycloalkyl group or a group of formula:—(CR²⁰R²¹)_(m)—(CR²²R²³)_(n)—(CR²⁴R²⁵)_(o)—NR²⁶R²⁷;

R² is selected from the group consisting of: H, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkoxyalkyl,R¹¹S(O)R¹³—, R¹¹S(O)₂R¹³—, R¹¹C(O)N(R¹²)R¹³—, R¹¹SO₂N(R¹²)R¹³—,R¹¹N(R¹²)C(O)R¹³—, R¹¹N(R¹²)SO₂R¹³—, R¹¹N(R¹²)C(O)N(R¹²)R¹³— and acyl,each of which may be optionally substituted;

R³ is selected from the group consisting of H, C₁-C₆ alkyl, and acyl,each of which may be optionally substituted;

X and Y are the same or different and are independently selected fromthe group consisting of: H, halogen, —CN, —NO₂, —CF₃, —OCF₃, alkyl,alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl,alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy,cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy,heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino,alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, —COOH—C(O)OR⁵,—COR⁵, —SH, —SR⁶, —OR⁶ acyl and —NR⁷R⁸, each of which may be optionallysubstituted;

R⁴ is selected from the group consisting of: H, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl andacyl, each of which may be optionally substituted;

each R⁵ is independently selected from the group consisting of: H,alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each ofwhich may be optionally substituted;

each R⁶ is independently selected from the group consisting of: H,alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each ofwhich may be optionally substituted;

each R⁷ and R⁸ is independently selected from the group consisting of:H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each ofwhich may be optionally substituted;

each R¹¹ and R¹² is independently selected from the group consisting ofH, alkyl, alkenyl, and alkynyl, each of which may be optionallysubstituted;

each R¹³ is a bond or is independently selected from the groupconsisting of: alkyl, alkenyl, and alkynyl, each of which may beoptionally substituted;

each R²⁰, R²¹, R²², R²³, R²⁴ and R²⁵ is independently selected from thegroup consisting of: H, halogen, —CN, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl,alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy,cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy,benzyloxy heteroaryloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl,aminosulfonyl, arylsulfonyl, arylsulfinyl-COOH, —C(O)OR⁵, —COR⁵, —SH,—SR³, —OR⁶ and acyl, each of which may be optionally substituted; or

R²⁰ and R²¹ when taken together may form a group of formula ═O or ═S,and/or

R²² and R²³ when taken together may form a group of formula ═O or ═S,and/or

R²⁴ and R²⁵ when taken together may form a group of formula ═O or ═S;

each R²⁶ and R²⁷ is independently selected from the group consisting of:H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy,heterocycloalkyloxy, aryloxy, arylalkyloxy, heteroaryloxy, amino,alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH,alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl,alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR⁵ and acyl,each of which may be optionally substituted,

or R²⁶ and R²⁷ when taken together with the nitrogen atom to which theyare attached form an optionally substituted heterocycloalkyl group;

Z is selected from the group consisting of —CH₂—, —CH₂CH₂—, —CH═CH—,C₃-C₆ alkylene, C₃-C₆ alkenylene, C₃-C₆ alkynylene, C₃-C₆ cycloalkyl,unsubstituted or substituted with one or more substituents independentlyselected from the group consisting of C₁-C₄ alkyl;

m, n and o are integers independently selected from the group consistingof 0, 1, 2, 3 and 4;

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment of the invention R⁴ is H and the compounds are thoseof formula (Ia):

or a pharmaceutically acceptable salt or prodrug thereof.

wherein R¹, R², R³, X, Y and Z are as defined for compounds of formula(I).

In another embodiment R³ and R⁴ are H and the compounds are of formula(Ib):

or a pharmaceutically acceptable salt or prodrug thereof

wherein R¹, R², X, Y and Z are as defined for compounds of formula (I).

As with any group of structurally related compounds which possess aparticular utility, certain groups are preferred for the compounds ofthe Formula (I), (Ia) and (Ib) in their end use application.

In one embodiment the group R¹ is a group of formula—(CR²⁰R²¹)_(m)—(CR²²R²³)_(n)—(CR²⁴R²⁵)_(o)—NR²⁶R²⁷;

in which m, n and o are integers independently selected from the groupconsisting of 0, 1, 2, 3 and 4.

Accordingly, in one embodiment the compounds of the invention arecompounds of formula (Ic):

wherein R¹ is a group of formula—(CR²⁰R²¹)_(m)—(CR²²R²³)_(n)—(CR²⁴R²⁵)_(o)—NR²⁶R²⁷

and R²R³, R⁴, X, Y, Z, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, m, n ando are as defined for compounds of formula (I).

As the values of m, n and o are integers ranging from 0 to 4 the sum ofm+n+o is an integer selected from the group consisting of 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, and 12. In one embodiment the sum of m+n+o is aninteger selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and8. In another embodiment the sum of m+n+o is an integer selected fromthe group consisting of 0, 1, 2, 3 and 4. In another embodiment the sumof m+n+o is an integer selected from the group consisting of 2 and 3.

In one specific embodiment the sum of m+n+o is 2. When this occurs R¹ isselected from the group consisting of:

-   -   —(CR²⁰R²¹)₂—NR²⁶R²⁷;    -   —(CR²²R²³)₂—NR²⁶R²⁷;    -   —(CR²⁴R²⁵)₂—NR²⁶R²⁷;    -   —(CR²⁰R²¹)—(CR²²R²³)—NR²⁶R²⁷;    -   —(CR²⁰R²¹)—(CR²⁴R²⁵)—NR²⁶R²⁷;    -   —(CR²²R²³)—(CR²⁴R²⁵)—NR²⁶R²⁷;

In one form of this embodiment R¹ is the group:—(CR²⁰R²¹)—(CR²²R²³)—NR²⁶R²⁷;

This provides compounds of the formula (II):

wherein X, Y, Z, R², R³, R⁴, R²⁰, R²¹, R²², R²³, R²⁶ and R²⁷ are asdefined in formula (I).

In a specific form of this embodiment R⁴ is H which provides compoundsof formula (IIa):

wherein X, Y, Z, R², R³, R²⁰, R²¹, R²², R²³, R²⁶ and R²⁷ are as definedin formula (I).

In another specific form R³ is H leading to compounds of formula (IIb):

wherein X, Y, Z, R², R²⁰R²¹R²²R²³R²⁶ and R²⁷ are as defined in formula(I).

In an even more specific form of this embodiment R²⁰, R²¹, R²² and R²³are H providing compounds of formula (IIc):

wherein X, Y, Z, R², R²⁶ and R²⁷ are as defined in formula (I).

In another embodiment the sum of m+n+o is 3. When this occurs R¹ isselected from the group consisting of:

-   -   —(CR²⁰R²¹)₃—NR²⁶R²⁷;    -   —(CR²²R²³)₃—NR²⁶R²⁷;    -   —(CR²⁴R²⁵)₃—NR²⁶R²⁷;    -   —(CR²⁰R²¹)₂—(CR²²R²³)—NR²⁶R²⁷;    -   —(CR²⁰R²¹)₂—(CR²⁴R²⁵)—NR²⁶R²⁷;    -   —(CR²⁰R²¹)—(CR²²R²³)₂—NR²⁶R²⁷;    -   —(CR²²R²³)₂—(CR²⁴R²⁵)—NR²⁶R²⁷;    -   —(CR²⁰R²¹)—(CR²⁴R²⁵)₂—NR²⁶R²⁷;    -   —(CR²²R²³)—(CR²⁴R²⁵)₂—NR²⁶R²⁷;    -   —(CR²⁰R²¹)—(CR²²R²³)—(CR²⁴R²⁵)—NR²⁶R²⁷;

In one form of this embodiment R¹ is a group of the formula:—(CR²⁰R²¹)—(CR²²R²³)—(CR²⁴R²⁵)—NR²⁶R²⁷.

This provides compounds of the formula (III):

wherein X, Y, Z, R², R³, R⁴, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶ and R²⁷are as defined in formula (I).

In a specific form of this embodiment R⁴ is H which provides compoundsof formula (IIIa).

wherein X, Y, Z, R², R³, R²⁰R²¹, R²², R²³, R²⁴, R²⁵, R²⁶ and R²⁷ are asdefined in formula (I).

In another specific form R³ is H leading to compounds of formula (IIIb):

wherein X, Y, Z, R², R²⁰R²¹, R²², R²³, R²⁴, R²⁵, R²⁶ and R²⁷ are asdefined in formula (I).

In an even more specific form of this embodiment R²⁰, R²¹, R²⁴ and R²⁵are H, and R²² and R²³ are methyl providing compounds of formula (IIIc).

wherein X, Y, Z, R², R²⁶ and R²⁷ are as defined in formula (I).

In each of the above embodiments of the invention R²⁰ and R²¹ mayrepresent a number of different variables. In one embodiment R²⁰ and R²¹are independently selected from the group consisting of H, alkyl,alkenyl and alkynyl. In another embodiment R²⁰ and R²¹ are independentlyselected from the group consisting of H and alkyl. In yet anotherembodiment R²⁰ and R²¹ are independently selected from the groupconsisting of H, methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl,3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl,pentyl, 2-methyl, pentyl, pent-4-enyl, hexyl, heptyl and octyl. In aspecific embodiment R²⁰ and R²¹ are both H.

In each of the above embodiments of the invention R²² and R²³ mayrepresent a number of different variables. In one embodiment R²² and R²³are independently selected is from the group consisting of H, alkyl,alkenyl and alkynyl. In another embodiment R²² and R²³ are independentlyselected from the group consisting of H and alkyl. In yet anotherembodiment R²² and R²³ are independently selected from the groupconsisting of H, methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl,3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl,pentyl, 2-methyl, pentyl, pent-4-enyl, hexyl, heptyl and octyl. In afurther embodiment R²² and R²³ are independently selected from the groupconsisting of alkyl. In a most specific embodiment R²² and R²³ are bothmethyl.

In each of the above embodiments of the invention R²⁴ and R²⁵ mayrepresent a number of different variables. In one embodiment R²⁴ and R²⁵are preferably independently selected from the group consisting of H,alkyl, alkenyl and alkynyl. In another embodiment R²⁴ and R²⁵ areindependently selected from the group consisting of H and alkyl. In yetanother embodiment R²⁴ and R²⁵ are independently selected from the groupconsisting of H, methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl,3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl,pentyl, 2-methyl, pentyl, pent-4-enyl, hexyl, heptyl and octyl. In aspecific embodiment R²⁴ and R²⁵ are both H.

In each of the above embodiments there are a number of values for R²⁶and R²⁷. In one embodiment R²⁶ and R²⁷ are independently selected fromthe group consisting of: H, alkyl, alkenyl, alkynyl, alkoxyalkyl, andacyl. In another embodiment R²⁶ and R²⁷ are independently selected fromthe group consisting of: H, alkyl and acyl. In a further embodiment R²⁶and R²⁷ are independently selected from the group consisting of H,methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl,butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl,pentyl, pent-4-enyl, hexyl, heptyl, octyl, acetyl and 2-methoxy-ethyl.

In another embodiment R¹ is a heterocycloalkyl group which mayoptionally be substituted.

In one form of this embodiment the heterocycloalkyl group is selectedfrom the group consisting of:

wherein R²⁸ is selected from the group consisting of H, halogen, alkyl,alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy,heterocycloalkyloxy, aryloxy, arylalkyloxy, heteroaryloxy, amino,alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH,alkoxycarbonyl, alkylaminocarbonyl, arylacyl, sulfonyl, alkylsulfonyl,alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR⁵ and acyl,each of which may be optionally substituted.

In one embodiment R²⁸ is selected from the group consisting of H, alkyl,alkenyl, arylalkyl and arylacyl. Specific values of R²⁸ are H, methyl;ethyl; propyl; 2-methyl-propyl, 2-2-dimethyl-propyl; isopropyl;3,3,3-trifluoro-propyl; butyl; isobutyl; 3,3-dimethyl-butyl; pentyl;2,4,4-trimethyl-pentyl; penten-4-yl, hexyl; heptyl, octyl, nonyl,2-methoxy nonyl, benzyl, 2-phenyl-ethyl, 2-phenyl-acetyl,3-phenyl-propyl,

In another embodiment the heterocycloalkyl group is pyrrolidyl,tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl,tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane,1,4-oxazepane, and 1,4-oxathiapane. In one specific embodiment R¹ isselected from the group consisting of piperidine-3-yl, piperidine-4-yland pyrollidin-3-y.

In another embodiment R¹ is a heteroaryl group.

In another embodiment R¹ is a group selected from the group consistingof:

In one specific embodiment R¹ is a group of formula:

In another specific embodiment R¹ is a group of formula:

In another specific embodiment R¹ is a group of formula:

In yet another specific embodiment R¹ is a group of formula:

In another specific embodiment R¹ is a group of formula:

In another specific embodiment R¹ is a group of formula:

In another specific embodiment R¹ is a group of formula:

In another specific embodiment R¹ is a group of formula:

In another specific embodiment R¹ is a group of formula:

In one embodiment R² is selected from the group consisting of H, alkyl,cycloalkyl, heteroalkyl, alkenyl, alkynyl, alkoxyalkyl andcycloalkylalkyl, each of which may be optionally substituted.

In one form of this embodiment R² is alkyl. In one embodiment the alkylis a C₁-C₁₀ alkyl. In another form of this embodiment the alkyl is aC₁-C₆ alkyl group. In another form of this embodiment R² is selectedfrom the group consisting of: methyl; ethyl; propyl; 2-methyl-propyl,2-2-dimethyl-propyl; isopropyl; 3,3,3-trifluoro-propyl; butyl; isobutyl;3,3-dimethyl-butyl; pentyl; 2,4,4-trimethyl-pentyl; hexyl; heptyl,octyl, nonyl, and 2-methoxy nonyl.

In one form of this embodiment R² is alkenyl. In one form of thisembodiment the alkenyl is a C₁-C₁₀ alkenyl. In another form of thisembodiment the alkenyl is a C₁-C₆ alkenyl group. In another form of thisembodiment R² is selected from the group consisting of: ethenyl,prop-1-enyl, prop-2-enyl, but-1-enyl, but-2-enyl but-3-enyl,pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, hex-1-enyl,hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-5-enyl.

In another embodiment R² is selected from the group consisting ofR¹¹S(O)R¹³—, R¹¹S(O)₂R¹³—, R¹¹C(O)N(R¹²)R¹³—, R¹¹SO₂N(R¹²)R¹³—,R¹¹N(R¹²)C(O)R¹³—, R¹¹N(R¹²)SO₂R¹³—, and R¹¹N(R¹²)C(O)N(R¹²)R¹³—. In oneform of this embodiment R² is a group of the formula R¹¹C(O)N(R¹²)R¹³—.In one form of this embodiment R¹³ is a C₁-C₆ alkyl. In a specific formof this embodiment R¹³ is methyl or ethyl. In one form of thisembodiment R¹² is H or C₁-C₆alkyl. A specific value for R¹² is H. In oneform of this embodiment R¹¹ is C₁-C₆ alkyl group. Specific values forR¹¹ include t-butyl and propyl. Specific examples of groups of this typeinclude: (CH₃)₃CCH₂CONH(CH₂)₂—; (CH₃)₃CCONH(CH₂)₂—; (CH₃)₃CCONH(CH₂)—and CH₃(CH₂)₂CONH(CH₂)—.

Specific values of R² are selected from the group consisting of: H;methyl; ethoxymethyl; [Bicylco[2.2.1]2-ylmethyl; Adamantan-2-ylmethyl;2-methansulfanyl-ethyl; 2,2,2-trifluoro-ethyl; propyl;2-2-dimethyl-propyl; isopropyl; 3,3,3-trifluoro-propyl; butyl; isobutyl;3,3-dimethyl-butyl; but-3-enyl; but-3-yny; pentyl;2,4,4-trimethyl-pentyl; Bicyclo[2.2.1]hept-5-en-2-yl; hexyl; hex-3-enyl;octyl; non-3-enyl; non-6-enyl; 2-methoxy-nonyl, 2-phenyl-cyclopropyl;cyclohexyl; (CH₃)₃CCH₂CONH(CH₂)₂—; (CH₃)₃CCONH(CH₂)₂—; (CH₃)₃CCONH(CH₂)—and CH₃(CH₂)₂CONH(CH₂)—.

In one embodiment X and Y may be the same or different and are selectedfrom the group consisting of H, halogen, C₁-C₄ alkyl, —CF₃, —NO₂,—C(O)R⁵, —OR⁶, —SR⁶, —CN and NR⁷R⁸.

In one embodiment X is H;

In one embodiment Y is H;

In one embodiment X and Y (if present) are at the 4 and 7 positions ofthe aromatic ring.

In one embodiment R³ is H, C₁-C₆ alkyl, or acyl. In another embodimentR³ is H or C₁-C₄ alkyl. A specific value for R³ is H;

In one embodiment R⁴ is H or C₁-C₄ alkyl. A specific value for R⁴ is H;

In one embodiment R⁵ is C₁-C₄ alkyl, heteroalkyl, or acyl. A specificvalue for R⁵ is methyl;

In one embodiment R⁶ is C₁-C₄ alkyl, heteroalkyl or acyl. A specificvalue for R⁶ is C₁-C₄ alkyl;

In one embodiment R⁷ and R⁸ are selected from the group consisting of H,C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉heterocycloalkyl, aryl, heteroaryl,arylalkyl, and heteroarylalkyl

Many if not all of the variables discussed above may be optionallysubstituted. If the variable is optionally substituted then in oneembodiment the optional substituent is selected from the groupconsisting of: halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl,alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl,alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy,cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy,heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino,alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, —COOH, —COR⁵,—C(O)OR⁵, —SH, —SR⁵, —OR⁶ and acyl.

In a further embodiment the optional substituents are selected from thegroup consisting of: halogen, ═O, ═S, —CN, —NO₂, alkyl, alkenyl,heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl,acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl,aminosulfonyl, —C(O)OR⁵, COOH, SH, and acyl.

In one embodiment the Z moiety is at the 5 or 6 position. In a specificembodiment the Z moiety is at the 5 position. In one embodiment the Zmoiety is a group of formula —CH═CH—. If the Z moiety is a group of thistype it is preferably in the “E” configuration.

In addition to compounds of Formula (I), the embodiments disclosed arealso directed to pharmaceutically acceptable salts, pharmaceuticallyacceptable prodrugs, and pharmaceutically active metabolites of suchcompounds, and pharmaceutically acceptable salts of such metabolites.Such compounds, salts, prodrugs and metabolites are at timescollectively referred to herein as “HDAC inhibiting agents” or “HDACinhibitors”.

The invention also relates to pharmaceutical compositions including acompound of the invention with a pharmaceutically acceptable carrier,diluent or excipient.

In yet a further aspect the present invention provides a method oftreatment of a disorder caused by, associated with or accompanied bydisruptions of cell proliferation and/or angiogenesis includingadministration of a therapeutically effective amount of a compound offormula (I). The embodiments disclosed also relate to pharmaceuticalcompositions each comprising a therapeutically effective amount of aHDAC inhibiting agent of the embodiments described with apharmaceutically acceptable carrier or diluent for treating cellularproliferative ailments, e.g., inhibition of proliferation of malignantcancer cells, benign tumor cells or other proliferative cells.

In one embodiment the method includes administration of a compound offormula (Ia) or (Ib) as described herein.

In one embodiment the disorder is selected from the group consisting ofbut not limited to cancer (e.g. breast cancer, colon cancer, prostatecancer, pancreatic cancer, leukemias, lymphomas, ovarian cancers,neuroblastomas, melanoma, inflammatory diseases/immune system disorders,angiofibroma, cardiovascular diseases (e.g. restenosis,arteriosclerosis), fibrotic diseases (e.g. liver fibrosis), diabetes,autoimmune diseases, chronic and acute neurodegenerative disease likedisruptions of nerval tissue, Huntington's disease and infectiousdiseases like fungal, bacterial and viral infections. In anotherembodiment the disorder is a proliferative disorder. In one embodimentthe proliferative disorder is cancer. The cancer can include solidtumors or hematologic malignancies.

The invention also provides agents for the treatment of a disordercaused by, associated with or accompanied by disruptions of cellproliferation and/or angiogenesis including a compound of formula (I) asdisclosed herein. In one embodiment the agent is an anti-cancer agent.In another embodiment the agent is an anti-angiogenesis agent.

In one embodiment the agent contains a compound of formula (Ia) or (Ib).

The invention also relates to the use of compounds of formula (I) in thepreparation of a medicament for the treatment of a disorder caused by,associated with or accompanied by disruptions of cell proliferationand/or angiogenesis. In one embodiment the disorder is a proliferativedisorder. In a specific embodiment the disorder is a cancer.

The compounds of the present invention surprisingly show low toxicity,together with a potent anti-proliferative activity.

In yet a further embodiment the invention provides a method of treatmentof a disorder, disease or condition that can be treated by theinhibition of histone deacetylase including administration of atherapeutically effective amount of a compound of formula (I).

In one embodiment the method includes administration of a compound offormula (Ia) or (Ib) as described herein.

In one embodiment the disorder is selected from the group consisting ofbut not limited to Proliferative disorders (e.g. cancer);Neurodegenerative diseases including Huntington's Disease, Polyglutaminediseases, Parkinson's Disease, Alzheimer's Disease, Seizures,Striatonigral degeneration, Progressive supranuclear palsy, Torsiondystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gillesde la Tourette syndrome, Diffuse Lewy body disease, Pick's disease,Intracerebral haemorrhage Primary lateral sclerosis, Spinal muscularatrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitialpolyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy,Hereditary spastic paraplegia, Progressive ataxia and Shy-Dragersyndrome; Metabolic diseases including Type 2 diabetes; DegenerativeDiseases of the Eye including Glaucoma, Age-related maculardegeneration, macular myopic degeneration, Rubeotic glaucoma,Interstitial keratitis, Diabetic retinopathy, Peter's anomaly retinaldegeneration, Cellophane Retinopathy; Cogan's Dystrophy; CornealDystrophy; Iris Neovascularization (Rubeosis); Neovascularization of theCornea; Retinopathy of Prematurity; Macular Edema; Macular Hole; MacularPucker; Marginal Blepharitis, Myopia, nonmalignant growth of theconjunctiva; Inflammatory diseases and/or Immune system disordersincluding Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronicarthritis, Graft versus Host disease, Psoriasis, Asthma,Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease,Colitis Ulcerosa, Alcoholic hepatitis, Diabetes, Sjoegrens's syndrome,Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy,Discogenic pain, Systemic Lupus Erythematosus, allergic contactdermatitis; Disease involving angiogenesis including cancer, psoriasis,rheumatoid arthritis; Psychological disorders including bipolar disease,schizophrenia, depression and dementia; Cardiovascular Diseasesincluding Heart failure, restenosis, cardiac hypertrophy andarteriosclerosis; Fibrotic diseases including liver fibrosis, lungfibrosis, cystic fibrosis and angiofibroma; Infectious diseasesincluding Fungal infections, such as Candida Albicans, Bacterialinfections, Viral infections, such as Herpes Simplex, Protozoalinfections, such as Malaria, Leishmania infection, Trypanosoma bruceiinfection, Toxoplasmosis and coccidiosis, and Haematopoietic disordersincluding thalassemia, anemia and sickle cell anemia.

The invention also provides agents for the treatment of a disorder,disease or condition that can be treated by the inhibition of histonedeacetylase including a compound of formula (I) as disclosed herein. Inone embodiment the agent is an anti-cancer agent.

The invention also relates to the use of compounds of formula (I) in thepreparation of a medicament for the treatment of a disorder, disease orcondition that can be treated by the inhibition of histone deacetylase.

The invention also provides a method for inhibiting cell proliferationincluding administration of an effective amount of a compound accordingto formula (I).

In yet an even further aspect the invention provides a method oftreatment of a neurodegenerative disorder in a patient includingadministration of a therapeutically effective amount of a compound offormula (I). In one embodiment the method includes administration of acompound of formula (Ia) or (Ib) as described herein. In one embodimentthe neurodegenerative disorder is Huntington's Disease.

The invention also provides agents for the treatment ofneurodegenerative disorder including a compound of formula (I) asdisclosed herein. In one embodiment the agent is preferablyanti-Huntington's disease agent.

The invention also relates to the use of compounds of formula (I) in thepreparation of a medicament for the treatment of a neurodegenerativedisorder. In one embodiment the neurodegenerative disorder isHuntington's Disease.

In yet an even further aspect the invention provides a method oftreatment of an inflammatory disease and/or immune system disorder in apatient including administration of a therapeutically effective amountof a compound of formula (I). In one embodiment the method includesadministration of a compound of formula (Ia) or (Ib) as describedherein.

In one embodiment the inflammatory disease and/or immune system disorderis rheumatoid arthritis. In another embodiment the inflammatory diseaseand/or immune system disorder is Systemic Lupus Erythematosus.

The invention also provides agents for the treatment of inflammatorydisease and/or immune system disorder including a compound of formula(I) as disclosed herein.

The invention also provides agents for the treatment of eye diseasemediated by HDAC inhibition including a compound of formula (I) asdisclosed herein. In one embodiment, the eye disease is maculardegeneration. In another embodiment, the eye disease is glaucoma. Inanother embodiment, the eye disease is retinal degeneration.

The invention also relates to the use of compounds of formula (I) in thepreparation of a medicament for the treatment of inflammatory diseaseand/or immune system disorder. In one embodiment the inflammatorydisease and/or immune system disorder is rheumatoid arthritis. Inanother embodiment the inflammatory disease and/or immune systemdisorder is Systemic Lupus Erythematosus.

The invention also provides methods of preparation of the compounds ofthe invention. In one embodiment the invention provides a method ofsynthesis of compounds of formula I as defined above the methodincluding:

(a) providing a compound of the formula (A1):

wherein X, Y and Z are as defined above and L is a leaving group;

(b) protecting the carboxyl group to produce a compound of the formula(A2):

wherein X, Y and Z are as defined above L is a leaving group and P^(c)is a carboxyl protecting group;

(c) displacing the leaving group with an amine of formula R¹NH₂ toproduce a compound of the formula (A3):

wherein X, Y, Z are as defined above, R¹ is as defined above or aprotected form thereof, and P^(c) is a carboxyl protecting group;

(d) optionally reacting the compound to further functionalise R¹;

(e) reducing the nitro group;

(f) reacting the reduced product with a compound of formula R²CO₂H or acompound of formula R²CHO and cyclising the product thus produced toproduce a compound of the formula (A4)

wherein X, Y, Z are as defined above, R¹ and R² are as defined above orprotected forms thereof, and P^(c) is a carboxyl protecting group;

(g) converting the compound to a compound of formula I;

wherein (d) can be carried out after any one of (c) (e) or (f) andfurther wherein (e) and (f) can be carried out sequentially orsimultaneously.

In yet an even further aspect the invention provides a method ofsynthesis of compounds of formula I as defined above

wherein R¹, R², R³, R⁴, X, Y and Z are as defined above, the methodincluding:

(a) providing an aldehyde of the formula (B1)

wherein R¹, R², X, and Y are as defined above;

(b) subjecting the aldehyde to reaction with an appropriatelysubstituted olefination agent to produce a compound of formula (B2)

wherein R¹, R², X, Y, and Z are as defined above, and P^(c) is H or acarboxyl protecting group;

(c) converting the compound to a compound of formula I.

In one embodiment of this method (a) includes:

(a1) providing a compound of the formula (B3):

wherein X and Y are as defined above, L is a leaving group and P^(c) isa carboxyl protecting group;

(a2) displacing the leaving group with an amine of formula R¹NH₂ toproduce a compound of the formula (B4):

wherein X, and Y are as defined above, R¹ is as defined above or aprotected form thereof, and P^(c) is a carboxyl protecting group

(a3) optionally reacting the compound to further functionalise R¹

(a4) reducing the nitro group;

(a5) reacting the reduced product with a compound of formula R²CO₂H or acompound of formula R²CHO and cyclising the product thus produced toproduce a compound of the formula (B5):

wherein X, and Y are as defined above, R¹ and R² are as defined above orprotected forms thereof, and P^(c) is a carboxyl protecting group

(a6) converting the compound of formula (B5) to the correspondingaldehyde

wherein (a3) can be carried out after any one of (a2), (a4), (a5) or(a6) and further wherein (a4) and (a5) may be carried out sequentiallyor simultaneously.

In yet an even further aspect the invention provides a method ofsynthesis of compounds of formula I as defined above

wherein R¹, R², R³, R⁴, X, Y and Z are as defined above, the methodincluding:

(a) providing a compound of the formula (C1)

wherein X, and Y are as defined above, R¹ and R² are as defined above orprotected forms thereof, and L¹ is a leaving group

(b) converting the compound (C1) to a compound of formula (C2);

wherein X, Y and Z are as defined above, R¹ and R² are as defined aboveor protected forms thereof, and P^(c) is H or a carboxyl protectinggroup

(c) converting the compound to a compound of formula I.

In one form of this embodiment (a) includes:

(a1) providing a compound of the formula (C3):

wherein X and Y are as defined above and L and L¹ are leaving groups;

(a2) displacing the leaving group (L) with an amine of formula R¹NH₂ toproduce a compound of the formula (C4):

wherein X and Y, are as defined above, R¹ is as defined above or aprotected form thereof, and L¹ is a leaving group;

(a3) optionally reacting the compound to further functionalise R¹;

(a4) reducing the nitro group;

(a5) reacting the reduced product with a compound of formula R²CO₂H or acompound of formula R²CHO and cyclising the product thus produced toproduce a compound of the formula (C1):

wherein (a3) can be carried out after any one of (a2), (a4) or (a5) andfurther wherein (a4) and (a5) may be carried out sequentially orsimultaneously.

DETAILED DESCRIPTION OF THE INVENTION

In this specification a number of terms are used which are well known toa skilled addressee. Nevertheless for the purposes of clarity a numberof terms will be defined.

As used herein, the term unsubstituted means that there is nosubstituent or that the only substituents are hydrogen.

The term “optionally substituted” as used throughout the specificationdenotes that the group may or may not be further substituted or fused(so as to form a condensed polycyclic system), with one or moresubstituent groups. Preferably the substituent groups are one or moregroups independently selected from the group consisting of halogen, ═O,═S, —ON, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl,heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl,heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,alkoxycycloalkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl,alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy,cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy,arylalkyloxy, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino,aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl,alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl,arylsulfinyl, aminosulfinylaminoalkyl, —COOH, —COR⁵, —C(O)OR⁵, CONHR⁵,NHCOR⁵, NHCOOR⁵, NHCONHR⁵, C(═NOH)R⁵, —SH, —SR⁵, —OR⁵ and acyl.

“Alkyl” as a group or part of a group refers to a straight or branchedaliphatic hydrocarbon group, preferably a C₁-C₁₄ alkyl, more preferablyC₁-C₁₀ alkyl, most preferably C₁-C₆ unless otherwise noted. Examples ofsuitable straight and branched C₁-C₆ alkyl substituents include methyl,ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and thelike. The group may be a terminal group or a bridging group.

“Alkylamino” includes both monoalkylamino and dialkylamino, unlessspecified. “Monoalkylamino” means a —NH-Alkyl group, in which alkyl isas defined above. “Dialkylamino” means a —N(alkyl)₂ group, in which eachalkyl may be the same or different and are each as defined herein foralkyl. The alkyl group is preferably a C₁-C₆ alkyl group. The group maybe a terminal group or a bridging group.

“Arylamino” includes both mono-arylamino and di-arylamino unlessspecified. Mono-arylamino means a group of formula aryl NH—, in whicharyl is as defined herein. di-arylamino means a group of formula (aryl₂)N— where each aryl may be the same or different and are each as definedherein for aryl. The group may be a terminal group or a bridging group.

“Acyl” means an alkyl-CO— group in which the alkyl group is as describedherein. Examples of acyl include acetyl and benzoyl. The alkyl group ispreferably a C₁-C₆ alkyl group. The group may be a terminal group or abridging group.

“Alkenyl” as a group or part of a group denotes an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and which may bestraight or branched preferably having 2-14 carbon atoms, morepreferably 2-12 carbon atoms, most preferably 2-6 carbon atoms, in thenormal chain. The group may contain a plurality of double bonds in thenormal chain and the orientation about each is independently E or Z.Exemplary alkenyl groups include, but are not limited to, ethenyl,propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. Thegroup may be a terminal group or a bridging group.

“Alkoxy” refers to an —O-alkyl group in which alkyl is defined herein.Preferably the alkoxy is a C₁-C₆alkoxy. Examples include, but are notlimited to, methoxy and ethoxy. The group may be a terminal group or abridging group.

“Alkenyloxy” refers to an —O— alkenyl group in which alkenyl is asdefined herein. Preferred alkenyloxy groups are C₁-C₆ alkenyloxy groups.The group may be a terminal group or a bridging group.

“Alkynyloxy” refers to an —O-alkynyl group in which alkynyl is asdefined herein. Preferred alkynyloxy groups are C₁-C₆ alkynyloxy groups.The group may be a terminal group or a bridging group.

“Alkoxycarbonyl” refers to an —C(O)—O-alkyl group in which alkyl is asdefined herein. The alkyl group is preferably a C₁-C₆ alkyl group.Examples include, but not limited to, methoxycarbonyl andethoxycarbonyl. The group may be a terminal group or a bridging group.

“Alkylsulfinyl” means a —S(O)-alkyl group in which alkyl is as definedabove. The alkyl group is preferably a C₁-C₆ alkyl group. Exemplaryalkylsulfinyl groups include, but not limited to, methylsulfinyl andethylsulfinyl. The group may be a terminal group or a bridging group.

“Alkylsulfonyl” refers to a —S(O)₂-alkyl group in which alkyl is asdefined above. The alkyl group is preferably a C₁-C₆ alkyl group.Examples include, but not limited to methylsulfonyl and ethylsulfonyl.The group may be a terminal group or a bridging group.

“Alkynyl as a group or part of a group means an aliphatic hydrocarbongroup containing a carbon-carbon triple bond and which may be straightor branched preferably having from 2-14 carbon atoms, more preferably2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.Exemplary structures include, but are not limited to, ethynyl andpropynyl. The group may be a terminal group or a bridging group.

“Alkylaminocarbonyl” refers to an alkylamino-carbonyl group in whichalkylamino is as defined above. The group may be a terminal group or abridging group.

“Cycloalkyl” refers to a saturated or partially saturated, monocyclic orfused or spiro polycyclic, carbocycle preferably containing from 3 to 9carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like, unless otherwise specified. It includesmonocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systemssuch as decalin, and polycyclic systems such as adamantane. The groupmay be a terminal group or a bridging group.

“Cycloalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem containing at least one carbon-carbon double bond and preferablyhaving from 5-10 carbon atoms per ring. Exemplary monocycliccycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.The cycloalkenyl group may be substituted by one or more substituentgroups. The group may be a terminal group or a bridging group.

The above discussion of alkyl and cycloalkyl substituents also appliesto the alkyl portions of other substituents, such as without limitation,alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl,alkylsulfonyl and alkyl ester substituents and the like.

“Cycloalkylalkyl” means a cycloalkyl-alkyl-group in which the cycloalkyland alkyl moieties are as previously described. Exemplarymonocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl and cycloheptylmethyl. The group may be a terminalgroup or a bridging group.

“Halogen” represents chlorine, fluorine, bromine or iodine.

“Heterocycloalkyl” refers to a saturated or partially saturatedmonocyclic, bicyclic, or polycyclic ring containing at least oneheteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10membered, more preferably 4 to 7 membered. Examples of suitableheterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl,tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl,morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and1,4-oxathiapane. The group may be a terminal group or a bridging group.

“Heterocycloalkenyl” refers to a heterocycloalkyl as described above butcontaining at least one double bond. The group may be a terminal groupor a bridging group.

“Heterocycloalkylalkyl” refers to a heterocycloalkyl-alkyl group inwhich the heterocycloalkyl and alkyl moieties are as previouslydescribed. Exemplary heterocycloalkylalkyl groups include(2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl. The groupmay be a terminal group or a bridging group.

“Heteroalkyl” refers to a straight- or branched-chain alkyl grouppreferably having from 2 to 14 atoms, more preferably 2 to 10 atoms inthe chain, one or more of which is a heteroatom selected from S, O, andN. Exemplary heteroalkyls include alkyl ethers, secondary and tertiaryalkyl amines, alkyl sulfides, and the like. The group may be a terminalgroup or a bridging group.

“Aryl” as a group or part of a group denotes (i) an optionallysubstituted monocyclic, or fused polycyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) preferably having from5 to 12 atoms per ring. Examples of aryl groups include phenyl,naphthyl, and the like; (ii) an optionally substituted partiallysaturated bicyclic aromatic carbocyclic moiety in which a phenyl and aC₅₋₇ cycloalkyl or C₅₋₇ cycloalkenyl group are fused together to form acyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. Thegroup may be a terminal group or a bridging group.

“Arylalkenyl” means an aryl-alkenyl-group in which the aryl and alkenylare as previously described. Exemplary arylalkenyl groups includephenylallyl. The group may be a terminal group or a bridging group.

“Arylalkyl” means an aryl-alkyl-group in which the aryl and alkylmoieties are as previously described. Preferred arylalkyl groups containa C₁₋₅ alkyl moiety. Exemplary arylalkyl groups include benzyl,phenethyl and naphthelenemethyl. The group may be a terminal group or abridging group.

“Arylacyl” means an aryl-acyl-group in which the aryl and acyl moietiesare as previously described. In general the aryl moiety is attached tothe alkyl portion of the acyl moiety, typically to the terminal carbonof the alkyl portion of the acyl moiety. Preferred arylacyl groupscontain a C₁₋₅ alkyl moiety in the acyl moiety. Exemplary arylacylgroups include 2-phenyl-acetyl. The group may be a terminal group or abridging group.

“Heteroaryl” either alone or part of a group refers to groups containingan aromatic ring (preferably a 5 or 6 membered aromatic ring) having oneor more heteroatoms as ring atoms in the aromatic ring with theremainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude nitrogen, oxygen and sulphur. Examples of heteroaryl includethiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan,isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole,1H-indazole, purine, quinoline, isoquinoline, phthalazine,naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine,acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole,isooxazole, furazane, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-,or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl1-, 2-, or 3-indolyl, and2-, or 3-thienyl. The group may be a terminal group or a bridging group.

“Heteroarylalkyl” means a heteroaryl-alkyl group in which the heteroaryland alkyl moieties are as previously described. Preferredheteroarylalkyl groups contain a lower alkyl moiety. Exemplaryheteroarylalkyl groups include pyridylmethyl. The group may be aterminal group or a bridging group.

“Lower alkyl” as a group means unless otherwise specified, an aliphatichydrocarbon group which may be straight or branched having 1 to 6 carbonatoms in the chain, more preferably 1 to 4 carbons such as methyl,ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl ortertiary-butyl). The group may be a terminal group or a bridging group.

In Formula (I), as well as in Formulae (Ia)-(Ib) defining sub-sets ofcompounds within Formula (I), there is shown a benzimidazole ringsystem. Within this ring system, there are substitutable positions atthe 4-, 5-, 6-, and 7-ring positions. In each of Formulae (I), (Ia), and(Ib), there is a requirement for attachment of an acidic moiety at oneof the ring positions. This acidic moiety may be provided by but is notlimited to groups containing, a hydroxamic acid or salt derivatives ofsuch acid which when hydrolysed would provide the acidic moiety. In someembodiments the acidic moiety may be attached to the ring positionthrough an alkylene group such as —CH₂— or —CH₂CH₂—, or an alkenylenegroup such as —CH═CH—. Preferred positions for attachment of the acidicmoiety are the 5- and 6-ring positions.

It is understood that included in the family of compounds of Formula (I)are isomeric forms including diastereoisomers, enantiomers, tautomers,and geometrical isomers in “E” or “Z” configurational isomer or amixture of E and Z isomers. It is also understood that some isomericforms such as diastereomers, enantiomers, and geometrical isomers can beseparated by physical and/or chemical methods and by those skilled inthe art.

Some of the compounds of the disclosed embodiments may exist as singlestereoisomers, racemates, and/or mixtures of enantiomers and/ordiastereomers. All such single stereoisomers, racemates and mixturesthereof are intended to be within the scope of the subject matterdescribed and claimed.

Additionally, Formula (I) is intended to cover, where applicable,solvated as well as unsolvated forms of the compounds. Thus, eachformula includes compounds having the indicated structure, including thehydrated as well as the non-hydrated forms.

In addition to compounds of the Formula (I), the HDAC inhibiting agentsof the various embodiments include pharmaceutically acceptable salts,prodrugs, and active metabolites of such compounds, and pharmaceuticallyacceptable salts of such metabolites.

The term “Pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the above-identified compounds, andinclude pharmaceutically acceptable acid addition salts and baseaddition salts. Suitable pharmaceutically acceptable acid addition saltsof compounds of Formula (I) may be prepared from an inorganic acid orfrom an organic acid. Examples of such inorganic acids are hydrochloric,sulfuric, and phosphoric acid. Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic andsulfonic classes of organic acids, examples of which are formic, acetic,propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Suitablepharmaceutically acceptable base addition salts of compounds of Formula(I) include metallic salts made from lithium, sodium, potassium,magnesium, calcium, aluminium, and zinc, and organic salts made fromorganic bases such as choline, diethanolamine, morpholine. Otherexamples of organic salts are: ammonium salts, quaternary salts such astetramethylammonium salt; amino acid addition salts such as salts withglycine and arginine. Additional information on pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,19th Edition, Mack Publishing Co., Easton, Pa. 1995. In the case ofagents that are solids, it is understood by those skilled in the artthat the inventive compounds, agents and salts may exist in differentcrystalline or polymorphic forms, all of which are intended to be withinthe scope of the present invention and specified formulae.

“Prodrug” means a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis, reduction or oxidation) to a compound offormula (I). For example an ester prodrug of a compound of formula (I)containing a hydroxyl group may be convertible by hydrolysis in vivo tothe parent molecule. Suitable esters of compounds of formula (I)containing a hydroxyl group, are for example acetates, citrates,lactates, tartrates, malonates, oxalates, salicylates, propionates,succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates,gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates,ethanesulphonates, benzenesulphonates, p-toluenesulphonates,cyclohexylsulphamates and quinates. As another example an ester prodrugof a compound of formula (I) containing a carboxy group may beconvertible by hydrolysis in vivo to the parent molecule. (Examples ofester prodrugs are those described by F. J. Leinweber, Drug Metab. Res.,18:379, 1987).

Preferred HDAC inhibiting agents include those having an IC₅₀ value of10 μM or less.

Specific compounds of the invention include the following:

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-isopropyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[2-Butyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2-methylsulfanyl-ethyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-ethoxymethyl-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diethylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Butyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-But-3-ynyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[2-But-3-enyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[2-But-3-enyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-But-3-ynyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diethylamino-ethyl)-2-ethoxymethyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-methyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diethylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]- acrylamide

3-[2-(2,2-Dimethyl-propyl)-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]- N-hydroxy-acrylamide

3-[2-Cyclohexyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[2-Bicyclo[2.2.1]hept-5-en-2-yl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Hex-3-enyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Hex-3-enyl-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Ethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]- acrylamide

3-[2-(2,2-Dimethyl-propyl)-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

N-Hydroxy-3-[2-isobutyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-acrylamide

3-[2-(2,2-Dimethyl-propyl)-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Ethylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]- acrylamide

3-[1-(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diethylamino-ethyl)-2-propyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Butyl-1-(2-diisopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Butyl-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-(2-methylsulfanyl-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[2-Butyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Butyl-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(1-Benzyl-piperidin-4-yl)-2-butyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-But-3-enyl-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Hexyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]- acrylamide

3-[1-(2-Dimethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Amino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Amino-ethyl)-2-(2-methoxy-nonyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Butyl-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Dimethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

N-{2-[1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2-yl]-ethyl}-3,3-dimethyl-butyramide

3-{1-(2-Diethylamino-ethyl)-2-[2-(2,2-dimethyl-propionylamino)-ethyl]-1H-benzoimidazol-5-yl}- N-hydroxy-acrylamide

3-{1-(2-Diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5- yl}-N-hydroxy-acrylamide

N-[1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2- ylmethyl]-butyramide

3-[1-(2-ethylamino-ethyl)-2-(3,3-dimethyl-butyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-(3,3-Dimethyl-butyl)-1-(2-Dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Dimethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

N-Hydroxy-3-[1-(5-methyl-1H-pyrazol-3-yl)-2-(2,4,4-trifmethyl-pentyl)-1H-benzoimidazol-5-yl]- acrylamide

3-[1-(2-Ethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-(2-Butyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide

3-(2-Butyl-1-piperidin-4-yl-1H-benzoimidazol-5- yl)-N-hydroxy-acrylamide

N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-acrylamide

N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-non-3-enyl-1H-benzoimidazol-5-yl]-acrylamide

N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-non-6-enyl-1H-benzoimidazol-5-yl]-acrylamide

3-[2-Hexyl-1-(2-methylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-acrylamide

N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-octyl-1H-benzoimidazol-5-yl]-acrylamide

3-[1-(2-Amino-ethyl)-2-octyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-{2-Butyl-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-{1-[2-(Ethyl-methyl-amino)-ethyl]-2-pentyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-(2-Hexyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide

3-[2-Butyl-1-(1-methyl-pyrrolidin-3-yl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-(2-Butyl-1-piperidin-3-yl-1H-benzoimidazol-5- yl)-N-hydroxy-acrylamide

3-(2-Hexyl-1-piperidin-3-yl-1H-benzoimidazol-5- yl)-N-hydroxy-acrylamide

3-(1-{2-[Ethyl-(2-methoxy-ethyl)-amino]-ethyl}-2-pentyl-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide

3-{2-Butyl-1-[2-(ethyl-methyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

N-Hydroxy-3-[1-(1-methyl-piperidin-3-yl)-2-pentyl-1H-benzoimidazol-5-yl]-acrylamide

3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-{1-[2-(Ethyl-pentyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-{1-[2-(Ethyl-heptyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

(E)-3-(2-hexyl-1-(1-(2-hydroxyethyl)piperidin-3-yl)-1H-benzo[d]imidazol-5-yl)-N- hydroxyacrylamide

3-(2-Butyl-1-{2-[ethyl-(3-hydroxy-propyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide

3-(1-{2-[Ethyl-(3-hydroxy-propyl)-amino]-ethyl}-2-pentyl-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide

(E)-N-hydroxy-3-(1-(1-phenethylpyrrolidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide

(E)-N-hydroxy-3-(1-(1-pentylpiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide

3-{1-[2-(Butyl-ethyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

(E)-N-hydroxy-3-(1-(1-phenethylpiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide

(E)-N-hydroxy-3-(1-(1-(3-phenylpropyl)piperidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide

(E)-N-hydroxy-3-(1-(1-(3-phenylpropyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide

3-{1-[1-(3,3-Dimethyl-butyl)-pyrrolidin-3-yl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

(E)-3-(1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide

3-[2-(4-Cyano-butyl)-1-(2-diethylamino-ethyl)-1H-benzoimidaozl-5-yl]-N-hydroxy-acrylamide

(E)-3-(1-(1-butylpiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide

(E)-N-hydroxy-3-(1-(1-(pent-4-enyl)piperidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide

(E)-3-(1-(1-(3,3-dimethylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide

3-[1-(2-Diethylamino-ethyl)-2-propylamino-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

(E)-N-hydroxy-3-(1-(2- (isopropyl(propyl)amino)ethyl)-1H-benzo[d]imidazol-5-yl)acrylamide

3-{1-[2-(Butyl-isopropyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

N-Hydroxy-3-{1-[2-(isopropyl-pentyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-acrylamide

3-[2-(5-Cyano-pentyl)-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-(1-{2-[(3,3-Dimethyl-butyl)-ethyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide

3-{1-[2-(Ethyl-propyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

N-Hydroxy-3-(1-{2-[isopropyl-(2-methyl-pentyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-acrylamide

(E)-N-hydroxy-3-(1-(2-(isopropyl(4,4,4-trifluorobutyl)amino)ethyl)-1H-benzo[d]imidazol- 5-yl)acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-propylamino-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-methyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-{1-[2-(Butyl-ethyl-amino)-ethyl]-2-trifluoromethyl-1H-benzoimidazol-5-yl}-N- hydroxy-acrylamide

3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-trifluoromethyl-1H-benzoimidazol-5-yl}-N- hydroxy-acrylamide

(E)-3-(1-(2-(dibutylamino)ethyl)-2-propyl-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide

3-[1-(2-Dipropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

N-Hydroxy-3-(1-{2-[isopropyl-(3-methyl-butyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-acrylamide

3-(1-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-ethyl}-1H-benzoimidaozl-5-yl)-N-hydroxy- acrylamide

3-(1-{2-[(2-Ethyl-butyl)-methyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide

(E)-3-(1-(2-(bis(3,3-dimethylbutyl)amino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide

(E)-3-(1-(2-(diisobutylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide

3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

N-Hydroxy-3-{1-[2-(methyl-pent-4-enyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-acrylamide

3-(1-{2-[(3,3-Dimethyl-butyl)-propyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-methylsulfanyl-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-propyl-1H-benzoimidazol-5-yl}-N-hydroxy- acrylamide

3-[1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[1-{2-[Bis-(3,3-dimethyl-butyl)-amino]-ethyl}-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-{1-[2-(2,2-Dimethyl-propylamino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-(1-{2-[(2,2-Dimethyl-propyl)-propyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide

3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-(1-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-ethyl}-2-propyl-1H-benzoimidazol-5-yl)-N- hydroxy-acrylamide

3-(1-{2-[(3,3-Dimethyl-butyl)-(2,2,2-trifluoro-ethyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N- hydroxy-acrylamide

3-(1-{2-[Butyl-(2,2,2-trifluoro-ethyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide

The compounds disclosed are hydroxamate compounds containing ahydroxamic acid type moiety in one of the substituents that may beinhibitors of deacetylases, including but not limited to inhibitors ofhistone deacetylases. The hydroxamate compounds may be suitable forprevention or treatment of a disorder caused by, associated with oraccompanied by disruptions of cell proliferation and/or angiogenesiswhen used either alone or together with a pharmaceutically acceptablecarrier, diluent or excipient. An example of such a disorder is cancer.

Administration of compounds within Formula (I) to humans can be by anyof the accepted modes for enteral administration such as oral or rectal,or by parenteral administration such as subcutaneous, intramuscular,intravenous and intradermal routes. Injection can be bolus or viaconstant or intermittent infusion. The active compound is typicallyincluded in a pharmaceutically acceptable carrier or diluent and in anamount sufficient to deliver to the patient a therapeutically effectivedose. In various embodiments the inhibitor compound may be selectivelytoxic or more toxic to rapidly proliferating cells, e.g. canceroustumors, than to normal cells.

As used herein the term ‘cancer’ is a general term intended to encompassthe vast number of conditions that are characterised by uncontrolledabnormal growth of cells.

It is anticipated that the compounds of the invention will be useful intreating various cancers including but not limited to bone cancersincluding Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like,brain and CNS tumours including acoustic neuroma, neuroblastomas, gliomaand other brain tumours, spinal cord tumours, breast cancers includingductal adenocarcinoma, metastatic ductal breast carcinoma, colorectalcancers, advanced colorectal adenocarcinomas, colon cancers, endocrinecancers including adenocortical carcinoma, pancreatic cancer, pituitarycancer, thyroid cancer, parathyroid cancer, thymus cancer, multipleendocrine neoplasma, gastrointestinal cancers including stomach cancer,esophageal cancer, small intestine cancer, liver cancer, extra hepaticbile duct cancer, gastrointestinal carcinoid tumour, gall bladdercancer, genitourinary cancers including testicular cancer, penilecancer, prostate cancer, gynaecological cancers including cervicalcancer, ovarian cancer, vaginal cancer, uterus/endometrium cancer, vulvacancer, gestational trophoblastic cancer, fallopian tube cancer, uterinesarcoma, head and neck cancers including oral cavity cancer, lip cancer,salivary gland cancer, larynx cancer, hypopharynx cancer, orthopharynxcancer, nasal cancer, paranasal cancer, nasopharynx cancer, leukemiasincluding childhood leukemia, acute lymphocytic leukemia, acute myeloidleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, acute promyelocytic leukemia, plasma cell leukemia,erythroleukemia, myelomas, haematological disorders includingmyelodysplastic syndromes, myeloproliferative disorders, aplasticanemia, Fanconi anemia, Waldenstroms Macroglobulinemia, lung cancersincluding small cell lung cancer, non-small cell lung cancer,mesothelioma, lymphomas including Hodgkin's disease, non-Hodgkin'slymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDSrelated Lymphoma, B-cell lymphoma, Burkitt's lymphoma, eye cancersincluding retinoblastoma, intraocular melanoma, skin cancers includingmelanoma, non-melanoma skin cancer, squamous cell carcinoma, merkel cellcancer, soft tissue sarcomas such as childhood soft tissue sarcoma,adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancersincluding kidney cancer, Wilms tumour, bladder cancer, urethral cancer,and transitional cell cancer.

Exemplary cancers that may be treated by the compounds of the presentinvention are breast cancer, lung cancer, ovarian cancer, prostatecancer, head and neck cancer, renal cancer (e.g. renal cell carcinoma),gastric cancer, colon cancer, colorectal cancer and brain cancer.

Exemplary cancers that may be treated by compounds of the presentinvention include but are not limited to leukemias such aserythroleukemia, acute promyelocytic leukemia, acute myeloid leukemia,acute lymphocytic leukemia, acute T-cell leukemia and lymphoma such asB-cell lymphoma (e.g. Burkitt's lymphoma), cutaneous T-cell lymphoma(CTCL), and peripheral T-cell lymphoma.

Exemplary cancers that may be treated by compounds of the presentinvention include solid tumors and hematologic malignancies. In anotherembodiment, preferred cancers that may be treated with the compounds ofthe present invention are colon cancer, prostate cancer, hepatoma andovarian cancer.

In another embodiment, exemplary cancers that may be treated with thecompounds of the present invention are non small cell lung cancer, smallcell lung cancer and mesothelioma.

In another embodiment, exemplary cancers that may be treated with thecompounds of the present invention are clear cellcarcinoma/mesonephroma, intestinal cancer and pancreatic cancer.

The compounds may also be used in the treatment of a disorder involving,relating to or, associated with dysregulation of histone deacetylase(HDAC).

There are a number of disorders that have been implicated by or known tobe mediated at least in part by HDAC activity, where HDAC activity isknown to play a role in triggering disease onset, or whose symptoms areknown or have been shown to be alleviated by HDAC inhibitors. Disordersof this type that would be expected to be amenable to treatment with thecompounds of the invention include the following but not limited to:Proliferative disorders (e.g. cancer); Neurodegenerative diseasesincluding Huntington's Disease, Polyglutamine diseases, Parkinson'sDisease, Alzheimer's Disease, Seizures, Striatonigral degeneration,Progressive supranuclear palsy, Torsion dystonia, Spasmodic torticollisand dyskinesis, Familial tremor, Gilles de la Tourette syndrome, DiffuseLewy body disease, Pick's disease, Intracerebral haemorrhage Primarylateral sclerosis, Spinal muscular atrophy, Amyotrophic lateralsclerosis, Hypertrophic interstitial polyneuropathy, Retinitispigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia,Progressive ataxia and Shy-Drager syndrome; Metabolic diseases includingType 2 diabetes; Degenerative Diseases of the Eye including Glaucoma,Age-related macular degeneration, macular myopic degeneration, Rubeoticglaucoma, Interstitial keratitis, Diabetic retinopathy, Peter's anomaly,retinal degeneration, Cellophane Retinopathy; Cogan's Dystrophy; CornealDystrophy; Iris Neovascularization (Rubeosis); Neovascularization of theCornea; Retinopathy of Prematurity; Macular Edema; Macular Hole; MacularPucker; Marginal Blepharitis, Myopia, nonmalignant growth of theconjunctiva; Inflammatory diseases and/or Immune system disordersincluding Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronicarthritis, Graft versus Host disease, Psoriasis, Asthma,Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease,Colitis Ulcerosa, Alcoholic hepatitis, Diabetes, Sjoegrens's syndrome,Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy,Discogenic pain, Systemic Lupus Erythematosus, allergic contactdermatitis; Disease involving angiogenesis including cancer, psoriasis,rheumatoid arthritis; Psychological disorders including bipolar disease,schizophrenia, depression and dementia; Cardiovascular Diseasesincluding Heart failure, restenosis, cardiac hypertrophy andarteriosclerosis; Fibrotic diseases including liver fibrosis, lungfibrosis, cystic fibrosis and angiofibroma; Infectious diseasesincluding Fungal infections, such as Candida Albicans, Bacterialinfections, Viral infections, such as Herpes Simplex, Protozoalinfections, such as Malaria, Leishmania infection, Trypanosoma bruceiinfection, Toxoplasmosis and coccidiosis, and Haematopoietic disordersincluding thalassemia, anemia and sickle cell anemia.

In using the compounds of the invention they can be administered in anyform or mode which makes the compound bioavailable. One skilled in theart of preparing formulations can readily select the proper form andmode of administration depending upon the particular characteristics ofthe compound selected, the condition to be treated, the stage of thecondition to be treated and other relevant circumstances. We refer thereader to Remingtons Pharmaceutical Sciences, 19^(th) edition, MackPublishing Co. (1995) for further information.

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition in combination with apharmaceutically acceptable carrier, diluent or excipient. The compoundsof the invention, while effective themselves, are typically formulatedand administered in the form of their pharmaceutically acceptable saltsas these forms are typically more stable, more easily crystallised andhave increased solubility.

The compounds are, however, typically used in the form of pharmaceuticalcompositions which are formulated depending on the desired mode ofadministration. As such in a further embodiment the present inventionprovides a pharmaceutical composition including a compound of Formula(I) and a pharmaceutically acceptable carrier, diluent or excipient. Thecompositions are prepared in manners well known in the art.

The invention in other embodiments provides a pharmaceutical pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention. In sucha pack or kit can be found a container having a unit dosage of the agent(s). The kits can include a composition comprising an effective agenteither as concentrates (including lyophilized compositions), which canbe diluted further prior to use or they can be provided at theconcentration of use, where the vials may include one or more dosages.Conveniently, in the kits, single dosages can be provided in sterilevials so that the physician can employ the vials directly, where thevials will have the desired amount and concentration of agent(s).Associated with such container(s) can be various written materials suchas instructions for use, or a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

The compounds of the invention may be used or administered incombination with one or more additional drug (s) that arechemotherapeutic drugs or HDAC inhibitor drugs and/or procedures (e.g.surgery, radiotherapy) for the treatment of the disorder/diseasesmentioned. The components can be administered in the same formulation orin separate formulations. If administered in separate formulations thecompounds of the invention may be administered sequentially orsimultaneously with the other drug(s).

In addition to being able to be administered in combination with one ormore additional drugs that include chemotherapeutic drugs or HDACinhibitor drugs the compounds of the invention may be used in acombination therapy. When this is done the compounds are typicallyadministered in combination with each other. Thus one or more of thecompounds of the invention may be administered either simultaneously (asa combined preparation) or sequentially in order to achieve a desiredeffect. This is especially desirable where the therapeutic profile ofeach compound is different such that the combined effect of the twodrugs provides an improved therapeutic result.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents that delay absorptionsuch as aluminium monostearate and gelatin.

If desired, and for more effective distribution, the compounds can beincorporated into slow release or targeted delivery systems such aspolymer matrices, liposomes, and microspheres.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

If desired, and for more effective distribution, the compounds can beincorporated into slow release or targeted delivery systems such aspolymer matrices, liposomes, and microspheres.

The active compounds can also be in microencapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Dosage forms for topical administration of a compound of this inventioninclude powders, patches, sprays, ointments and inhalants. The activecompound is mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers, or propellantswhich may be required.

The term “therapeutically effective amount” or “effective amount” is anamount sufficient to effect beneficial or desired results. An effectiveamount can be administered in one or more administrations. An effectiveamount is typically sufficient to palliate, ameliorate, stabilize,reverse, slow or delay the progression of the disease state. Atherapeutically effective amount can be readily determined by anattending diagnostician by the use of conventional techniques and byobserving results obtained under analogous circumstances. In determiningthe therapeutically effective amount a number of factors are to beconsidered including but not limited to, the species of animal, itssize, age and general health, the specific condition involved, theseverity of the condition, the response of the patient to treatment, theparticular compound administered, the mode of administration, thebioavailability of the preparation administered, the dose regimeselected, the use of other medications and other relevant circumstances.

A preferred dosage will be a range from about 0.01 to 300 mg perkilogram of body weight per day. A more preferred dosage will be in therange from 0.1 to 100 mg per kilogram of body weight per day, morepreferably from 0.2 to 80 mg per kilogram of body weight per day, evenmore preferably 0.2 to 50 mg per kilogram of body weight per day. Asuitable dose can be administered in multiple sub-doses per day.

As discussed above, the compounds of the embodiments disclosed inhibithistone deacetylases. The enzymatic activity of a histone deacetylasecan be measured using known methodologies [Yoshida M. et al, J. Biol.Chem., 265, 17174 (1990), J. Taunton et al, Science 1996 272: 408]. Incertain embodiments, the histone deacetylase inhibitor interacts withand/or reduces the activity of more than one known histone deacetylasein the cell, which can either be from the same class of histonedeacetylase or different class of histone deacetylase. In some otherembodiments, the histone deacetylase inhibitor interacts and reduces theactivity of predominantly one histone deacetylase, for example HDAC-1,HDAC-2, HDAC-3 or HDAC-8 which belongs to Class I HDAC enzymes [DeRuijter A. J. M. et al, Biochem. J., 370, 737-749 (2003)]. HDACs canalso target non-histone substrates to regulate a variety of biologicalfunctions implicated in disease pathogenesis. These non-histonesubstrates include Hsp90, α-tubulin, p53, NFkb and HIF1a [Drummond etal., Annu. Rev. Pharmacol. Toxicol. 45:495 (2004)]. Certain preferredhistone deacetylase inhibitors are those that interact with, and/orreduce the activity of a histone deacetylase which is involved intumorigenesis, and these compounds may be useful for treatingproliferative diseases. Examples of such cell proliferative diseases orconditions include cancer (include any metastases), psoriasis, andsmooth muscle cell proliferative disorders such as restenosis. Theinventive compounds may be particularly useful for treating tumors suchas breast cancer, colon cancer, lung cancer, ovarian cancer, prostatecancer, head and/or neck cancer, or renal, gastric, pancreatic cancerand brain cancer as well as hematologic malignancies such as lymphomasand leukemias. In addition, the inventive compounds may be useful fortreating a proliferative disease that is refractory to the treatmentwith other chemotherapeutics; and for treating hyperproliferativecondition such as leukemias, psoriasis and restenosis. In otherembodiments, compounds of this invention can be used to treat pre-cancerconditions or hyperplasia including familial adenomatous polyposis,colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia,endometrial hyperplasia with atypia, cervical dysplasia, vaginalintraepithelial neoplasia, benign prostatic hyperplasia, papillomas ofthe larynx, actinic and solar keratosis, seborrheic keratosis andkeratoacanthoma. In a preferred embodiment, exemplary pre-cancerconditions or hyperplasia that can be treated by compounds of thisinvention are familial adenomatous polyposis, colonic adenomatous polypsand myeloid dysplasia.

Additionally compounds of the various embodiments disclosed herein maybe useful for treating neurodegenerative diseases, and inflammatorydiseases and/or immune system disorders.

In one embodiment the disorder is selected from the group consisting ofcancer, inflammatory diseases and/or immune system disorders (e.g.rheumatoid arthritis, systemic lupus erythematosus), angiofibroma,cardiovascular diseases, fibrotic diseases, diabetes, autoimmunediseases, chronic and acute neurodegenerative disease like Huntington'sdisease, Parkinson's disease, disruptions of nerval tissue andinfectious diseases like fungal, bacterial and viral infections. Inanother embodiment the disorder is a proliferative disorder. In yetanother embodiment, the proliferative disorder is cancer.

The histone deacetylase inhibitors of the invention have significantanti-proliferative effects and promote differentiation, cell cyclearrest in the G1 or G2 phase, and induce apoptosis.

Synthesis of Deacetylase Inhibitors

The present invention also provides a number of synthetic routes tosynthesize the compounds of the invention.

In one embodiment the method of synthesis of compounds of formula I asdefined above

includes: (a) providing a compound of the formula (A1):

(b) protecting the carboxyl group to produce a compound of the formula(A2):

(c) displacing the leaving group with an amine of formula R¹NH₂ toproduce a compound of the formula (A3):

(d) optionally reacting the compound to further functionalise R¹

(e) reducing the nitro group;

(f) reacting the reduced product with a compound of formula R²CO₂H or acompound of formula R²CHO and cyclising the product thus produced toproduce a compound of the formula (A4):

(g) converting the compound to a compound of formula I;

wherein (d) can be carried out after any one of (c) (e) or (f) andfurther wherein (e) and (f) can be carried out sequentially orsimultaneously.

The reaction sequence employed above typically utilises a carboxylprotecting group. The term “protecting group” refers to a chemical groupthat exhibits the following characteristics: 1) reacts selectively withthe desired functionality in good yield to give a protected substratethat is stable to the projected reactions for which protection isdesired; 2) is selectively removable from the protected substrate toyield the desired functionality; and 3) is removable in good yield byreagents compatible with the other functional group(s) present orgenerated in such projected reactions. Examples of suitable protectinggroups can be found in Greene et al. (1991) Protective Groups in OrganicSynthesis, 2nd Ed. (John Wiley & Sons, Inc., New York). A number of wellknown carboxyl protecting groups may be used and the methodology chosento attach the protecting group will depend upon the choice of protectinggroup to be used as would be well understood by a skilled addressee inthe art. In one embodiment the protecting group is an alkyl protectinggroup to form the ether. These may be produced in a number of wayshowever it is typically found that they can be readily accessed viareaction of the free acid with an alcohol under acidic conditions. Anexample of a suitable alcohol for this purpose is methanol however otheralcohols such as ethanol, propanol, butanol and the like may also beused.

The reaction sequence detailed above also takes advantage of a suitablylocated leaving group on the starting material to facilitate reactionwith the amine in (b). A leaving group is a chemical group that isreadily displaced by the desired incoming chemical moiety. Accordinglyin any situation the choice of leaving group will depend upon theability of the particular group to be displaced by the incoming chemicalmoiety. Suitable leaving groups are well known in the art, see forexample “Advanced Organic Chemistry” Jerry March 4^(th) Edn. pp 351-357,Oak Wick and Sons NY (1997). Examples of suitable leaving groupsinclude, but are not limited to, halogen, alkoxy (such as ethoxy,methoxy), sulphonyloxy, optionally substituted arylsulfonyl and thelike. Specific examples include chloro, iodo, bromo, fluoro, ethoxy,methoxy, methonsulphonyl, triflate and the like. It is preferred thatthe leaving group is either chloro or bromo. The displacement of theleaving group typically is carried out by reaction of the compoundcontaining the leaving group with a nucleophile such as an amine whichundergoes nucleophilic aromatic substitution to displace the leavinggroup. This typically involves reaction of the compound containing theleaving group in a non-interfering solvent with an excess of amine. Theamine may vary and is typically chosen to provide the appropriatesubstitution pattern after displacement of the leaving group. Thesubstitution reaction may also be catalysed by any of a number ofcatalysts well known in the art such as palladium, copper and the like.

In some embodiments it may be desired to then further functionalise theR¹ group introduced in the displacement either at this stage or at alater stage in the synthesis. This may be achieved in a number of waysdepending upon the exact functionality of the R¹ group introduced. Forexample if the R¹ group contains an NH group then it may be furtherreacted with other agents to add additional functionality. For exampleit may be reacted with an acid, an acid chloride or an acid anhydrideunder standard conditions to introduce an amide linkage. Alternativelyit may be reacted with an aldehyde under reducing conditions (reductiveamination) to form an alkyl amine (via the imine). Alternatively it maybe reacted with an alkylating agent such as an alkyl halide to producethe corresponding alkylated amine. The amine may also be reacted with anaryl or alkyl sulphonyl chloride to introduce an aryl or alkyl sulphonylgroup onto the amine. It may also be that the amine introduced is in aprotected form in which case the amine protecting group may need to beremoved under standard conditions prior to the modifications discussedabove being carried out. If this is done the protecting group istypically removed under standard conditions (depending upon the exactnature of the protecting group) and then reacted as discussed above.

The reaction sequence also involves a reduction of the nitro group.Reduction of the nitro group may be carried out using any technique wellknown in the art. For example it may be reduced using strong reducingagents such as LiAlH₄ or NaBH₄ (typically in an alcoholic solvent). Itmay also be achieved by reaction with triphenyl phosphine in water or byreaction with SnCl₂ or Zn (typically in an alcoholic solvent or aceticacid or a combination thereof). The reduction may be conducted in anysuitable solvent although it is typically conducted in a hydroxylicsolvent such as methanol or ethanol in the presence of acetic acid.

The process then typically involves reaction of the reduced nitro moietywith a carboxyl group or an aldehyde to produce a product which is thencyclised to produce the cyclised product. This typically involvesaddition of a stoichiometric amount of the carboxyl group or thealdehyde to a solution of the di-amine under suitable reactionconditions. These conditions typically induce dehydration of thereaction product such as Dean-and-Stark apparatus or the presence of acoupling agent such as DCC.

The reduction of the nitro moiety to produce a reduced product and thereaction of the reduced product with a carbonyl moiety (acid oraldehyde) followed by intramolecular cyclisation may be carried out in asequential fashion or they may be carried out simultaneously in aone-pot operation.

The synthesis involves conversion of the compounds thus formed into thecompounds of the invention. This may be carried out in a number of waysbut is most conveniently achieved by reaction with hydroxylaminehydrochloride to produce the free hydroxamic acid. Entry to otherhydroxamic acid species within the scope of the invention may be readilyachieved through the use of different hydroxylamine derivatives.

In another embodiment the method of synthesis of compounds of formula Ias defined above

includes: (a) providing an aldehyde of the formula (B1)

(b) subjecting the aldehyde to reaction with an appropriatelysubstituted olefination agent to produce a compound of formula (B2)

(c) converting the compound to a compound of formula I.

This sequence employs an olefination to introduce the desiredfunctionality to the six membered ring. The olefination agent used maybe any olefination agent well known in the art. In one embodiment theolefination agent is a Wittig reagent (a phosphorous ylide orphosphorane). Reagents of this type are readily accessible by reactionof a phosphonium salt with a base. In another embodiment the olefinationagent is a Horner Emmons or Wadsworth Emmons reagent which is aphosphonate ylide (RO)₂P(O)—CH₂R which can readily be accessed via theArbuzov reaction. In each of these instances the reaction is carried outunder standard conditions. Judicious selection of the reagent allows fora wide variety of products to be accessed.

As with the earlier sequence the product is then converted to thecompounds of the invention using the techniques described above.

The aldehyde used as the starting material in the sequence describedabove may be provided using any methodology well known in the art. Inone embodiment the aldehyde is produced by

(1) providing a compound of the formula (B3) as described above

(2) converting the compound to the aldehyde.

The compound (B5) may be converted to the aldehyde via a variety oftechniques well known in the art. In one embodiment the conversionincludes first reducing the protected carboxyl group to the alcoholfollowed by oxidation of the alcohol. The reduction of the carboxylgroup may be carried out using any technique well known in the art. Forexample it may include treatment of the protected carboxyl group with astrong reducing agent such as DIBAL, LiAlH₄, LiBH₄, lithium trimethylborohydride, BH₃—SMe₂ (in refluxing THF) and triethoxysilane in anon-interfering solvent. Alternatively, rather than reducing theprotected carboxyl group all the way to the alcohol it may beselectively reduced directly to the aldehyde using standard conditions.

Once the alcohol has been obtained it may be oxidised to the aldehydeusing a number of techniques well known in the art. This may involvereaction of the alcohol with oxidants such as acid dichromate, KMnO₄,Br₂, MnO₂, ruthenium tetroxide and the like. The reaction may also becarried out by the use of Jones reagent. The conversion may also becarried out by catalytic dehydrogenation or by reaction with agents suchas N-bromosuccinimide or related compounds. These oxidation conditionsare typically carried out under standard conditions.

The compound of formula (B5) may be provided in any way well known inthe art. In one embodiment providing the compound of formula (B5)includes (1) providing a compound of formula (B4)

(2) reducing the nitro group;

(3) reacting the reduced product with a compound of formula R²CO₂H or acompound of formula R²CHO and cyclising the product thus produced toproduce (B5).

The reduction of the nitro compound and the reaction of the reducedproduct thus produced followed by cyclisation are typically carried outusing the methodologies as discussed above.

Providing a compound of formula (B4) generally includes (1) providing acompound of the formula (B3):

(2) displacing the leaving group with an amine of formula R¹NH₂ toproduce a compound of the formula (B4): The reaction of the amine todisplace the leaving group typically occurs in the presence of a base.Any suitable base may be used with examples of suitable bases includinghindered tertiary amines, alkali earth metal carbonates and anyinorganic base, which is compatible with protected carboxylic group byway of example. Specific bases include sodium carbonate, sodiumbicarbonate, potassium carbonate and potassium bicarbonate.

In another embodiment the invention provides a method of synthesis ofcompounds of formula I as defined above

(a) providing a compound of the formula (C1)

(b) converting the compound of formula (C1) to a compound of formula(C2);

(c) converting the compound to a compound of formula I.

Conversion of the compound of formula (C1) to a compound of formula (C2)may be carried out using any of a wide range of conditions well known inthe art. In general any electrophilic aromatic substitution reaction maybe used to introduce the desired functionality. An example of a suitablereaction is a Heck reaction.

The compound of formula (C1) may be provided by (1) providing a compoundof formula (C4) and converting a compound of formula (C4) to a compoundof formula (C1). This typically involves (a4) reducing the nitro groupto produce a reduced product and reacting the reduced product with acompound of formula R²CO₂H or a compound of formula R²CHO followed byintramolecular cyclisation of the product thus produced to produce acompound of the formula (C1). These processes are typically carried outusing the methodology as discussed above.

The compound of formula (C4) is typically provided by providing acompound of the formula (C3):

and displacing the leaving group (L) with an amine of formula R¹NH₂ toproduce a compound of the formula (C4):

The displacement reaction is typically carried out using the methodologyas discussed above.

The agents of the various embodiments may be prepared using the reactionroutes and synthesis schemes as described below, employing thetechniques available in the art using starting materials that arereadily available. The preparation of particular compounds of theembodiments is described in detail in the following examples, but theartisan will recognize that the chemical reactions described may bereadily adapted to prepare a number of other agents of the variousembodiments. For example, the synthesis of non-exemplified compounds maybe successfully performed by modifications apparent to those skilled inthe art, e.g. by appropriately protecting interfering groups, bychanging to other suitable reagents known in the art, or by makingroutine modifications of reaction conditions. A list of suitableprotecting groups in organic synthesis can be found in T. W. Greene'sProtective Groups in Organic Synthesis, 3^(rd) Edition, John Wiley &Sons, 1991. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds of the various embodiments.

Reagents useful for synthesizing compounds may be obtained or preparedaccording to techniques known in the art.

In the examples described below, unless otherwise indicated, alltemperatures in the following description are in degrees Celsius and allparts and percentages are by weight, unless indicated otherwise.

Various starting materials and other reagents were purchased fromcommercial suppliers, such as Aldrich Chemical Company or LancasterSynthesis Ltd., and used without further purification, unless otherwiseindicated. Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) werepurchased from Aldrich in SureSeal bottles and used as received. Allsolvents were purified by using standard methods in the art, unlessotherwise indicated.

The reactions set forth below were performed under a positive pressureof nitrogen, argon or with a drying tube, at ambient temperature (unlessotherwise stated), in anhydrous solvents, and the reaction flasks arefitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven-dried and/or heat-dried. Analyticalthin-layer chromatography was performed on glass-backed silica gel 60 F254 plates (E Merck (0.25 mm)) and eluted with the appropriate solventratios (v/v). The reactions were assayed by TLC and terminated as judgedby the consumption of starting material.

The TLC plates were visualized by UV absorption or with a p-anisaldehydespray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20 wt% in ethanol) which was activated with heat, or by staining in iodinechamber. Work-ups were typically done by doubling the reaction volumewith the reaction solvent or extraction solvent and then washing withthe indicated aqueous solutions using 25% by volume of the extractionvolume (unless otherwise indicated). Product solutions were dried overanhydrous sodium sulfate prior to filtration, and evaporation of thesolvents was under reduced pressure on a rotary evaporator and noted assolvents removed in vacuo. Flash column chromatography [Still et al, J.Org. Chem., 43, 2923 (1978)] was conducted using Silica gel 60 (MerckKGaA, 0.040-0.063 mm, 230-400 mesh ASTM) and a silica gel:crude materialratio of about 20:1 to 50:1, unless otherwise stated. Hydrogenolysis wasdone at the pressure indicated or at ambient pressure.

NMR spectra were recorded on a Bruker AVANCE 400 spectrometer operatingat 400 MHz for ¹H NMR and 100 MHz for ¹³C-NMR. NMR spectra are obtainedas CDCl₃ solutions (reported in ppm), using chloroform as the referencestandard (7.26 ppm and 77.14 ppm) or CD₃OD (3.3 and 49.3 ppm), orDMSO-d₆ (2.50 and 39.5 ppm) or an internal tetramethylsilane standard(0.00 ppm) when appropriate. Other NMR solvents were used as needed.When peak multiplicities are reported, the following abbreviations areused: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,br=broadened, dd=doublet of doublets, dt=doublet of triplets. Couplingconstants, when given, are reported in Hertz.

Mass spectra were obtained using LC/MS either in ESI or APCI. Allmelting points are uncorrected.

All final products had greater than 90% purity (by HPLC at wavelengthsof 254 nm and/or 220 nm). Analytical HPLC conditions for purity check:Xterra® RP18 3.5 μm 4.6×20 mm IS column; 2.0 ml/min, gradient 5-65% Bover 4 min, then 65-95% b over 1 min and 95% B for additional 0.1 min;Solvent A: H₂O with 0.1% trifluoroacetic acid (TFA); Solvent B:acetonitrile with 0.1% TFA.

The following examples are intended to illustrate the embodimentsdisclosed and are not to be construed as being limitations thereto.Additional compounds, other than those described below, may be preparedusing the following described reaction scheme or appropriate variationsor modifications thereof.

Synthesis

Schemes I and II illustrate the procedures used for preparing compoundsof formula Ib, wherein X and Y are hydrogens, compounds (VII) of formulaIa can be prepared by analogous procedure, for example, by the choice ofappropriate starting material. For example, in the case of Z is —CH═CH—and attached to C₅-position in Formula Ib, such compound(s) can besynthesized by analogous method illustrated in Scheme I and II startingwith a substituted cinnamic acid (e.g. trans-3-nitro-4-chloro-cinnamicacid), appropriate amine component (R¹NH₂), carboxylic acid component(R²CO₂H, Scheme I) or aldehyde (R²CHO, Scheme II), and appropriatehydroxylamine or N-alkyl hydroxylamine (NHR³OH where R³ is defined asabove in Formula Ia).

Specifically, the hydroxamate compounds Formula Ib can be synthesized bythe synthetic route shown in Scheme I. The reaction oftrans-4-chloro-3-nitrocinnamic acid (I) with an amine R¹NH₂ in thepresence of a base (e.g. triethylamine) in an appropriate solvent (e.g.dioxane) gave (II). Treatment of (II) in methanol under acid catalysis(e.g. sulfuric acid) resulted in esterification providing (III).Alternatively, the carboxylic acid (I) may be esterified to the methylester (Ia) and then the chloride was replaced by the appropriate aminecomponent R¹NH₂ to give compound (III). The nitro group of (III) can bereduced by appropriate reducing agent (e.g. tin (II) chloride) and theresulting phenylenediamine (IV) was coupled with an acid R²CO₂H to giveamide (V) which was subsequently cyclized in an appropriate solvent(e.g. acetic acid) to give benzimidazole (VI) (J. Med. Chem. 2001, 44,1516-1529). The hydroxamate compounds (VI) were obtained from methylester (VI) by a known synthesis method (J. Med. Chem., 2002, 45,753-757).

Alternatively, as depicted in Scheme II, compound (VI) was prepared byreacting with an appropriate aldehyde component R²CHO in the presence ofa reducing agent of nitro group (e.g. tin (II) chloride, or zinc powder)in one-pot (Tetrahedron Letters, 2000, 41, 9871-9874). Formic acid wasused to prepare compound (VI) when R²═H.

In both Schemes I & II, the benzimidazole ring may be constructed by acyclization step involving either an aldehyde or a carboxylic acid. Thefollowing reaction steps 1-4 refer to the use of carboxylic acid for thecyclization of (IV) via (V) to form benzimidazole derivatives (VI),followed by the conversion of ester (VI) to the hydroxamate (VII). Forone-pot cyclization of (III) to (VI), see the procedures under Example1.

Step 1: Reduction of Nitro Group

To a pre-stirred solution of starting material (III, 1.0 mmol) in 50 mLof co-solvent (glacial acetic acid: methanol=2:8), Tin chloride wasadded (5.0 mmol). The resulting solution was heated to 55° C. overnightand then cooled to room temperature. The solvent was removed and themixture was neutralized with sodium bicarbonate to pH 8. The crudeproduct was extracted with dichloromethane (20 mL) for three times. Theorganic extracts were combined and washed with water (15 mL) twice andbrine (15 mL) once and further dried over Na₂SO₄ for 1 hour. It wasfiltered and concentrated; the diamino product (IV) was purified byflash chromatography.

Step 2: Amide Formation

To a pre-stirred solution of carboxylic acid (1.1 mmol), diamino product(IV, 1.0 mmol) and PyBOP (1.1 mmol) in 10 mL of dried dichloromethane,was added DIEA (3.0 mmol) via a syringe. The resulting mixture wasstirred at room temperature for 4 hours. The amide product (V) waspurified by silica gel column chromatography.

Step 3: Cyclization

The amide product (V), obtained in Step 2, was treated with 5 mL ofglacial acetic acid, the resulting solution was heated to 75° C. for 24hours. After cooling down to rt, the solvent was removed under vacuum togive product (VI) near quantitatively.

Step 4: Hydroxamic Acid Formation

To a stirred solution of ester (VI) and NH₂OH.HCl (10 equiv.) in MeOH(0.5 M) was added NaOMe solution (20 equiv.) at −78° C. The reactionmixture was then allowed to warm up slowly to room temperature. Thereaction was monitored by LC/MS and was completed in around 15˜60 min.1N HCl was then added slowly into the reaction mixture at 0° C. Thedesired product was separated by reverse-phase preparative HPLC and thefractions containing the desired product were freeze-dried. Thehydroxamate product (VI) was obtained as TFA salt (isolated yield variesbetween 40-70%).

Scheme III illustrates another alternative procedure used for preparingcompounds of formula Ib, where X and Y are hydrogens and R² is selectedfrom the group R¹¹S(O)R¹³—, R¹¹S(O)₂R¹³—, R¹¹C(O)N(R¹²)R¹³—,R¹¹SO₂N(R¹²)R¹³—, R¹¹N(R¹²)C(O)R¹³—, R¹¹N(R¹²)SO₂R¹³—,R¹¹N(R¹²)C(O)N(R¹²)R¹³— and heteroalkyl. For example, in the case of Zis —CH═CH— and attached to C₅-position in Formula Ib, such compound(s)(XIII) can be synthesized by analogous method illustrated in Schemes I &starting with appropriate (III), appropriate Fmoc protected amino acids,appropriate acid chlorides or aldehydes, and hydroxylamine.

More specifically, for example, the hydroxamate compounds Formula Ib,where X and Y are hydrogens, R² is selected from the group R¹¹S(O)R¹³—,R¹¹S(O)₂R¹³—, R¹¹C(O)N(R¹²)R¹³—, R¹¹SO₂N(R¹²)R¹³—, R¹¹N(R¹²)C(O)R¹³—,R¹¹N(R¹²)SO₂R¹³—, R¹¹N(R¹²)C(O)N(R¹²)R¹³— and heteroalkyl; and Z isattached to C₅-position, can be synthesized by the synthetic route shownin Scheme III. Appropriate intermediate (III) was reduced with tinchloride to the corresponding diamines (IV). The coupling reaction withappropriate Fmoc protected amino acids in the presence of PyBOP gavecoupling product(s) (VIII) and/or (IX). Without further separation,(VIII) and/or (IX) were subjected to cyclization under acid conditionsand yielded benzimidazole (X). The key intermediate (XI) can be obtainedby treating (X) with 20% piperidine. Treatment of (XI) with anappropriate acid chloride or an appropriate sulfonyl chloride gave (XII)and the target compounds (XIII) were obtained by using similar methoddescribed in Scheme I.

When (XI) was reacted with an appropriate aldehyde under reductionconditions (NaBH(OAc)₃/CH₃CO₂H), (XIV) was obtained and can betransformed to corresponding hydroxamate derivatives (XV) by the samemethods described above.

Scheme IV illustrates some reactions to further modify R¹ side chain. Ifthe R¹ side chain contained a protecting group such as Boc in compound(VIa1), it could be removed before converting to the final hydroxamicacid (VIIa). The intermediate (VIa) could be modified by acylation,reductive alkylation, alkylation or sulfonylation to form new analogs(VIIb, VIIc, VIId and VIIe) through new intermediates (VIb, VIc, VId andVIe). The above described methods were also applied to R¹=heterocycles,e.g., R¹═N-Boc-piperidin-3-yl, N-Boc-piperidin-4-yl andN-Boc-pyrrolidin-3-yl.

Scheme V illustrates some alternative method to prepare (VIa) and (VIc).The primary amine (IIIa2) was prepared either from (Ia) or via (IIIa1).The derivertization of the amino group (e.g., reductive amination) couldbe performed either from (IIIa2) or (VIa2). The products, i.e.,(IIIa2-1) and (VIa2-1), could be further derivertized (e.g., reductiveamination of the secondary amine).

Scheme VI and VII illustrate some alternative methods to prepare (VI) byforming the benzimidazole ring first and introducing the double bondlater.

In Scheme VI, compound (XVI) was reacted with an amine R¹NH₂ in thepresence of a base (e.g. triethylamine) in an appropriate solvent (e.g.dioxane) to give (XVII). Benzimidazole (XVIII) ring was formed byreacting compound (XVII) with aldehyde R²CHO in the presence of areducing agent of nitro group (e.g. tin (II) chloride, zinc powder orother appropriate reducing agent) in one-pot. The ester (XVIII) wasconverted to the aldehyde (XX) via a reduction and oxidation process.Finally, (VI) was obtained by reacting aldehyde (XX) with a Wittig orWittig-Horner reagent.

In Scheme VII, compound (XXI) was reacted with an amine R¹NH₂ in thepresence of a base (e.g. triethylamine) in an appropriate solvent (e.g.dioxane) to give (XXII). Benzimidazole (XXIII) ring was formed byreacting compound (XXII) with aldehyde R²CHO in the presence of areducing agent of nitro group (e.g. tin (II) chloride, zinc powder orother appropriate reducing agent) in one-pot. Finally, the bromide(XXIII) was converted to (VI) under Heck reaction condition.

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thesubject matter hereof. They should not be considered as limiting thescope of the disclosure, but merely as being illustrative andrepresentative thereof.

Preparation of Intermediates III

Compound (III) was prepared either from (I) via (II) or from (I) via(Ia) (Scheme I and V). The following are examples of (III).

Intermediate 1 3-[4-(2-Dimethylamino-ethylamino)-3-nitro-phenyl]-acrylicacid methyl ester

A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (Ia,0.658 g, 2.72 mmol), N,N-dimethylethylenediamine (0.90 mL, 8.20 mmol)and triethylamine (1.2 mL, 8.6 mmol) in dioxane (20 mL) was heated at80° C. for 5 h. The solution was evaporated and the residue was addedDCM and aqueous Na₂CO₃. The DCM (×3) extracts were concentrated and theresidue was added EtOAc-hexane. The resulting red solid was filtered togive the titled compound (0.672 g, 84.2%). HPLC purity at 254 nm: 99.2%,t_(R)=1.59 min. LCMS (ESI) m/z: 294 ([M+H]⁺). ¹H NMR (CDCl₃+CD₃OD) δ8.21 (1H, d, J=2.1 Hz), 7.56 (1H, dd, J=9.0, 2.1 Hz), 7.48 (1H, d,J=16.0 Hz), 6.81 (1H, d, J=9.0 Hz), 6.20 (1H, d, J=15.9 Hz), 3.70 (3H,s), 3.34 (2H, t, J=6.5 Hz), 2.56 (2H, t, J=6.4 Hz), 2.23 (6H, s); ¹³CNMR (CDCl₃+CD₃OD) δ 167.3, 145.4, 142.6, 134.0, 131.1, 127.1, 121.3,114.8, 114.0, 56.7, 51.1, 44.6, 40.1.

Intermediate 2 3-[4-(2-Diethylamino-ethylamino)-3-nitro-phenyl]-acrylicacid methyl ester

Yellow solid. LCMS (ESI) m/z: 322 ([M+H]⁺). ¹H NMR (CDCl₃) δ 8.73 (1H,t-like, J=4.3 Hz), 8.32 (1H, d, J=2.0 Hz), 7.62 (1H, dd, J=9.2, 2.0 Hz),7.58 (1H, d, J=15.9 Hz), 6.85 (1H, d, J=9.0 Hz), 6.29 (1H, d, J=15.9Hz), 3.80 (3H, s), 3.35 (2H, td, J=5.4, 6.0 Hz), 2.77 (2H, t, J=6.2 Hz),2.59 (4H, q, J=7.1 Hz), 1.07 (6H, t, J=7.1 Hz).

Intermediate 3 3-[4-(2-Ethylamino-ethylamino)-3-nitro-phenyl]-acrylicacid methyl ester

Red solid. LCMS (ESI) m/z: 294 ([M+H]⁺). ¹H NMR (DMSO-d₆) δ 8.49 (1H, t,J=6.1 Hz), 8.35 (1H, d, J=2.0 Hz), 7.96 (1H, dd, J=9.1, 1.9 Hz), 7.62(1H, d, J=16.0 Hz), 7.20 (1H, d, J=9.1 Hz), 6.52 (1H, d, J=16.0 Hz),3.75 (2H, td, J=6.5, 6.2 Hz), 3.70 (3H, s), 3.08 (2H, t, J=6.5 Hz), 2.93(4H, q, J=7.2 Hz), 1.17 (6H, t, J=7.2 Hz).

Intermediate 43-[4-(2-Isopropylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methylester

Red solid. LCMS (ESI) m/z: 308 ([M+H]⁺). ¹H NMR (DMSO-d₆) δ8.58 (1H, t,J=5.6 Hz), 8.33 (1H, d, J=2.0 Hz), 7.94 (1H, dd, J=9.1, 1.9 Hz), 7.60(1H, d, J=16.0 Hz), 7.14 (1H, d, J=9.2 Hz), 6.49 (1H, d, J=16.0 Hz),3.70 (3H, s), 3.56 (2H, masked by water peak, identified by COSY), 3.10(1H, septet, J=6.4 Hz), 2.94 (2H, t, J=6.2 Hz), 1.10 (6H, d, J=6.4 Hz).

Intermediate 53-[4-(3-Dimethylamino-2,2-dimethyl-propylamino)-3-nitro-phenyl]-acrylicacid methyl ester

Red solid. LCMS (ESI) m/z: 336 ([M+H]⁺). ¹H NMR (CDCl₃) δ 9.73 (1H, br sor t), 8.33 (1H, d, J=2.0 Hz), 7.60 (1H, dd, J=8.9, 2.0 Hz), 7.59 (1H,d, J=16.1 Hz), 6.88 (1H, d, J=9.1 Hz), 6.28 (1H, d, J=15.9 Hz), 3.80(3H, s), 3.21 (2H, d, J=4.6 Hz), 2.36 (2H, s), 2.34 (6H, s), 1.04 (6H,s).

Intermediate 63-[4-(2-Diisopropylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methylester

Yellow solid. LCMS (ESI) m/z: 350 ([M+H]⁺). ¹H NMR (CDCl₃) δ 8.76 (1H,t-like, J=4.3 Hz), 8.32 (1H, d, J=2.0 Hz), 7.61 (1H, dd, J=8.3, 2.7 Hz),7.58 (1H, d, J=15.8 Hz), 6.85 (1H, d, J=9.0 Hz), 6.29 (1H, d, J=15.9Hz), 3.79 (3H, s), 3.31 (2H, td, J=5.3, 6.1 Hz), 3.08 (2H, septet, J=6.6Hz), 2.84 (2H, t, J=6.2 Hz), 1.07 (12H, d, J=6.6 Hz).

Intermediate 7 3-[4-(2-Methylamino-ethylamino)-3-nitro-phenyl]-acrylicacid methyl ester

Red solid. LCMS (ESI) m/z: 280 ([M+H]⁺). ¹H NMR (CDCl₃) δ 8.54 (1H,t-like, J=4.2 Hz), 8.33 (1H, d, J=2.1 Hz), 7.63 (1H, dd, J=9.0, 2.2 Hz).7.59 (1H, d, J=16.0 Hz), 6.90 (1H, d, J=9.0 Hz), 6.31 (1H, d, J=15.9Hz), 3.80 (3H, s), 3.45 (2H, td, J=5.8, 5.6 Hz), 2.96 (2H, t, J=6.2 Hz),2.50 (3H, s).

Intermediate 83-[4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-phenyl]-acrylicacid methyl ester (IIIa1)

Step 1:

A suspension of trans-4-chloro-3-nitrocinnamic acid (I, 5.057 g, 22.22mmol) in MeOH (40 mL) and DCM (20 mL) was stirred and cooled in adry-ice/acetone bath. SOCl₂ (1.0 mL, 13.8 mmol) was added to the abovemixture. Dry-ice bath was removed, then the mixture was warmed to roomtemperature and stirred at 40° C. till the reaction completed. Thesolution was evaporated to dryness to a pale yellow solid (5.364 g,99.9%). HPLC purity at 254 nm: 99.5%; t_(R)=2.96 min. LCMS (ESI) m/z:210 and 212 (very weak signal, [M+H-MeOH]⁺).

Step 2:

A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (Ia,0.243 g, 1.00 mmol), N-Boc-ethylenediamine (0.316 mL, 2.0 mmol) andtriethylamine (0.50 mL, 3.59 mmoL) in dioxane (7 mL) was heated at 80°C. for about 80 h. The solution was evaporated and the residue was addedMeOH. The resulting solid was filtered and washed with MeOH.3-[4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-phenyl]-acrylicacid methyl ester (IIIa1) was obtained as bright yellow solid (0.193 g,52.6%). HPLC purity at 254 nm: 96.0˜98.1%; t_(R)=3.27 min. LCMS (ESI)m/z: 366 ([M+H]⁺), 310 (M+H-56), 266 (M+H-Boc). ¹H NMR (CDCl₃) δ 8.41(1H, br t like, NHAr), 8.31 (1H, d, J=1.8 Hz), 7.63 (1H, dd, J=9.0, 1.7Hz), 7.57 (1H, d, J=16.0 Hz), 6.98 (1H, d, J=8.9 Hz), 6.30 (1H, d,J=15.9 Hz), 3.80 (3H, s), 3.52 (2H, m), 3.45 (2H, m), 1.45 (9H, s); ¹³CNMR (CDCl₃) δ 166.9, 155.7, 145.8, 142.3, 134.1, 131.5, 127.1, 121.8,115.4, 113.9, 79.5, 51.2, 42.7, 39.1, 27.9.

Intermediate 9 3-[4-(2-Amino-ethylamino)-3-nitro-phenyl]-acrylic acidmethyl ester (IIIa2)

Method 1:

Remove Boc protecting group from (IIIa1) under acidic condition: 1)HCl/MeOH; 2) TFA/DCM.

Method 2:

To the ester (Ia, 2.47 g, 10.2 mmol) in dioxane (102 mL, 0.1 M) wasadded ethylenediamine (Merck. Product no. 8.00947, 2.04 mL, 30.6 mmol)followed by triethylamine (2.8 mL, 20.47 mmol). The resulting mixturewas heated to 90° C. and stirred for 20 hours. The completion ofreaction was confirmed by using HPLC (where the product IIIa2 t_(R)=1.6min, starting material Ia t_(R)=3.1 min). Upon completion, solvent wasremoved and the crude was dissolved in DCM. The solution was washed withwater, brine, dried over Na₂SO₄ and filtered. The filtrate after removalof the solvent gave the titled compound IIIa2. Yield=98%, LCMS m/z: 266([M+H]⁺).

EXAMPLE 1 Preparation of3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(1)

The titled compound (1) was prepared according to Scheme 1 and II, byusing appropriate starting materials.

Step 1:

To a pre-stirred solution of trans-4-chloro-3-nitrocinnamic acid (I, 11g, 48 mmol) in dioxane (200 mL) was added triethylamine (20 mL, 126mmol), followed by 3-dimethylamino-2,2-dimethyl-propylamine (20 mL, 143mmol). The reaction mixture was allowed to stir at 100° C. for 1-2 daystill all starting material was fully converted. Then, the solvent wasremoved under vacuum followed by the addition of H₂O (250 mL) todissolve the residue. Conc. HCl was added till pH≈1 with orangeprecipitation. The suspension was filtered and residue was washed withH₂O several times to obtain (II) as orange solid (13 g, 84%). LCMS (ESI)m/z: 322 ([M+H]⁺).

Step 2:

Compound (II, 13 g, 40.5 mmol) was dissolved in MeOH (250 mL) followedby the addition of conc. H₂SO₄ (5 mL). The reaction mixture was allowedto stir at 80° C. for 18 h. Solvent was removed under vacuum and H₂O(250 mL) was added to dissolve the residue. Na₂CO₃ was added tillpH≈8-9, subsequently, MeOH was added and stirred for 1 hour. Then, thesuspension was filtered under vacuo and the residue was washed with H₂Oseveral times to obtain ester (III) as orange solid (10 g, 74%). LCMS(ESI) m/z: 336 ([M+H]⁺).

Step 3:

To a stirred solution of ester (III, 1 equiv) and SnCl₂.2H₂O (5 equiv)in AcOH and MeOH (0.2 M, 1:9 mixture) was added 3,3-dimethylbutyraldehyde (1.5 equiv). The resulting mixture was heated to 45° C.with stirring. The progress of the reaction was monitor by LC/MS. Whenthe reaction was completed, solvent was removed under reduced pressureat 30-35° C. To the resulting residue, 20 mL of water and 20 mL of ethylacetate were added at room temperature, the pH value of the mixture wascarefully adjusted to 9-10 by addition of conc. NH₃.H₂O. The mixture wasstirred for half an hour, followed by centrifuge if necessary toseparate the organic layer. The organic layer was collected. The aqueousphase and residue (oily-solid precipitate) were extracted another 3times more with ethyl acetate as described above. The combined organiccontents were dried over sodium sulphate, filtered and evaporated todryness. The resulting oily residue was purified by flash columnchromatography (isolated yield of cyclized product (VI) varies between50-90%). LCMS (ESI) m/z: 386 ([M+H]⁺).

Step 4:

To a stirred solution of ester (VI) and NH₂OH.HCl (10 equiv.) in MeOH(0.5M) was added NaOMe (20 equiv.) at −78° C. The reaction mixture wasthen allowed to warm up slowly to room temperature. The reaction wasmonitored by LC/MS and was completed in around 15 min. 1N HCl was thenadded slowly into the reaction mixture at 0° C. The desired product wasseparated by prep-HPLC and the fractions containing the desired productwere freeze-dried. Product (VII) was obtained as TFA salt (isolatedyield varies between 40-70%). HPLC purity at 254 nm: 100%, t_(R)=0.78min. LCMS (ESI) m/z: 387 ([M+H]⁺). ¹H NMR (DMSO-d₆) δ 1.05 (15H, s),2.91 (6H, s), 2.92 (2H, s), 3.32 (2H, bs), 4.35 (2H, s), 6.49 (1H, d,J=15.8 Hz), 7.56 (1H, d, J=9.0 Hz), 7.61 (1H, d, J=15.76 Hz), 7.83 (1H,d, J=9.0 Hz), 7.85 (1H, s), 9.22 (1H, bs), 10.72 (1H, bs); ¹³C NMR(DMSO-d₆) δ 162.6, 154.2, 138.0, 135.3 (br), 134.7, 131.5, 122.8, 119.2,115.2, 114.0, 66.5, 51.1, 46.7, 38.4, 38.3, 33.6, 29.1, 22.8.

EXAMPLE 2 Preparation of3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-isopropyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(2)

The titled compound (2) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 100%, t_(R)=0.54 min. LCMS (ESI) m/z: 359 ([M+H]⁺). ¹HNMR (DMSO-d₆) δ 1.05 (6H, s), 1.40 (6H, d, J=6.36 Hz), 2.92 (6H, s),3.36 (2H, s), 3.58 (1H, m, J=6.4 Hz), 4.44 (2H, s), 6.55 (1H, d, J=15.8Hz), 7.63 (1H, d, J=15.8 Hz), 7.66 (1H, d, J=8.7 Hz), 7.95 (1H, d, J=8.7Hz), 7.90 (1H, s), 9.71 (1H, bs), 10.80 (1H, bs).

EXAMPLE 3 Preparation of3-[2-Butyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(3)

The titled compound (3) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. Yield:74 mg as TFA salt. HPLC purity at 254 nm: 99.0%, t_(R)=0.89 min. LCMS(ESI) m/z: 373 ([M+H]⁺). ¹H NMR (CD₃OD) δ 7.99 (1H, d, J=8.8 Hz), 7.84(1H, s), 7.72 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=15.8 Hz), 6.53 (1H, d,J=15.7 Hz), 4.55 (2H, s), 3.43 (2H, s), 3.24 (2H, overlapped withCD2HOD), 3.00 (6H, s), 1.90 (2H, pentet, J=7.2 Hz), 1.49 (2H, m), 1.21(6H, s), 0.98 (3H, t, J=7.3 Hz); ¹³C NMR (CD₃OD) δ 165.5 (br), 158.2,139.8, 135.3, 135.1, 132.4, 126.4, 120.6 (br), 115.6, 114.3, 68.7, 53.5,47.8 (Me×2), 39.5, 29.9, 27.2, 23.6 (Me×2), 23.3, 13.9.

EXAMPLE 4 Preparation of3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2-methylsulfanyl-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(4)

The titled compound (4) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. Yield:17 mg as TFA salt. HPLC purity at 254 nm: 96.2%, t_(R)=0.75 min. LCMS(ESI) m/z: 391 ([M+H]⁺). ¹H NMR (CD₃OD) δ 8.02 (1H, d, J=8.3 Hz), 7.92(1H, s), 7.80 (1H, d, J=8.7 Hz), 7.69 (1H, d, J=15.8 Hz), 6.60 (1H, d,J=15.8 Hz), 4.49 (2H, s), 3.50 (2H, t, J=7.2 Hz), 3.37 (2H, s), 3.03(2H, t, J=7.2 Hz), 2.95 (6H, s), 2.18 (3H, s), 1.25 (6H, s); ¹³C NMR(CD₃OD) δ 163.7, 154.6, 138.2, 133.9, 132.8, 132.5, 124.1, 118.2, 113.3,113.2, 66.7, 51.5, 45.9 (Me×2), 37.6, 29.9, 26.2, 21.7 (Me×2), 13.7.

EXAMPLE 5 Preparation of3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(6)

The titled compound (6) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 96.2%, t_(R)=0.82 min. LCMS (ESI) m/z: 373 ([M+H]⁺).¹H NMR (DMSO-d₆): δ 10.80 (1H, s), 9.47 (1H, s), 7.93 (1H, s), 7.90 (1H,d, J=6.6 Hz), 7.64 (1H, d, J=7.4 Hz), 7.62 (1H, d, J=15.5 Hz), 6.54 (1H,d, J=15.8 Hz), 4.39 (2H, s), 3.33 (2H, s), 2.97 (2H, d, J=7.26 Hz), 2.92(6H, s), 2.35 (1H, qn), 1.09 (6H, s), 0.97 (6H, d, J=6.6 Hz).

EXAMPLE 6 Preparation of3-[1-(2-Diethylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(7)

The titled compound (7) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.0%, t_(R)=0.56 min. LCMS (ESI) m/z: 359 ([M+H]⁺).¹H NMR (DMSO-d₆): δ 10.81 (1H, s), 10.13 (1H, s), 7.90 (1H, s), 7.81(1H, d, J=8.5 Hz), 7.66 (1H, d, J=8.6 Hz), 7.61 (1H, d, J=15.8 Hz), 6.53(1H, d, J=15.8 Hz), 4.72 (2H, t, J=7.8 Hz), 3.30 (2H, d), 2.93 (2H, d,J=7.2 Hz), 2.27 (1H, m), 1.24 (6H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz)¹³C NMR (DMSO-d₆) δ 162.7, 158.5, 158.2, 155.2, 138.4, 133.9, 131.0,123.0, 118.6, 116.0, 111.6, 48.8, 46.8, 34.1, 27.1, 22.2, 8.5.

EXAMPLE 7 Preparation of3-[2-Butyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(8)

The titled compound (8) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. Yield:61 mg (20% in two steps) as TFA salt. HPLC purity at 254 nm: 98.1%,t_(R)=0.59 min. LCMS (ESI) m/z: 359 ([M+H]⁺). ¹H NMR (CD₃OD) δ 7.94 (1H,d, J=8.6 Hz), 7.85 (1H, s), 7.76 (1H, d, J=8.5 Hz), 7.50 (1H, d, J=15.7Hz), 6.49 (1H, d, J=15.7 Hz), 4.96 (2H, overlapped with DHO, identifiedby COSY), 3.69 (2H, t-like, J=7.6 Hz), 3.44 (4H, q, J=7.6 Hz), 3.26 (2H,t, J=7.9 Hz), 1.94 (2H, pentet, J=7.5 Hz), 1.57 (2H, m), 1.40 (6H, t,J=7.2 Hz), 1.05 (3H, t, J=7.3 Hz); ¹³C NMR (CD₃OD) δ 165.5, 157.7,140.0, 134.8, 134.0, 133.8, 126.5, 119.9, 115.1, 113.6, 50.2, 48.7 (2C),40.5, 29.4, 26.6, 23.3, 13.9, 8.9 (2C). (TFA peak 163.4, 163.0, 162.7,162.3; 122.3, 119.5, 116.6).

Dihydrochloride salt of 8 was prepared according to the proceduresdescribed in Example 50, Step 4 and 5, by using appropriate startingmaterials. ¹H NMR (DMSO-d₆) δ 11.79 (brs, 1H), 10.92 (very br s, 1H),8.18 (1H, d, J=8.6 Hz), 7.97 (1H, s), 7.79 (1H, d, J=8.6 Hz), 7.64 (1H,d, J=15.8 Hz), 6.65 (1H, d, J=15.8 Hz), 5.01 (2H, t-like, J=7.7 Hz),3.48 (2H, m), 3.30-3.19 (6H, m), 1.87 (2H, pentet, J=7.8 Hz), 1.47 (2H,sextet, J=7.5 Hz), 1.29 (6H, t, J=7.2 Hz), 0.97 (3H, t, J=7.3 Hz); ¹³CNMR (DMSO-d₆) δ 162.3, 156.0, 137.3 (CH), 132.8, 132.3, 132.0 (br,identified by HMBC), 124.7 (CH), 120.2 (CH), 113.1 (2×CH), 48.2, 46.3,39.0, 28.1, 25.0, 21.7, 13.6, 8.3.

EXAMPLE 8 Preparation of3-[2-But-3-ynyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(9)

The titled compound (9) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 98.3%; t_(R)=0.52 min; LCMS (ESI) m/z: 369 ([M+H]⁺).¹H NMR (DMSO-d₆) δ 9.49 (brs, 1H), 7.88-7.85 (m, 2H), 7.63-7.59 (m, 2H),6.52 (d, J=15.79 Hz, 1H), 4.37 (s, 1H), 3.33 (s, 2H), 3.26 (t, J=7.24Hz, 2H), 2.92 (s, 6H), 2.88 (t, J=2.54 Hz, 1H), 2.81 (dt, J=2.48, 7.70Hz, 2H), 1.09 (s, 6H); ¹³C NMR (DMSO-d₆) δ 162.8, 155.3, 138.4, 138.0,135.9, 130.5, 122.3, 118.4, 117.8, 116.4, 114.9, 112.9, 111.9, 82.8,72.3, 66.9, 50.9, 46.7, 25.8, 22.8, 16.2.

EXAMPLE 9 Preparation of3-[2-But-3-enyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(10)

The titled compound (10) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99%; t_(R)=0.80 min; LCMS (ESI) m/z: 371 ([M+H]⁺). ¹HNMR (CD₃OD) δ 7.95 (d, J=8.8 Hz, 1H), 7.85 (s, 1H), 7.73 (d, J=8.8 Hz,1H), 7.63 (d, J=15.8 Hz, 1H), 6.54 (d, J=15.8 Hz, 1H), 5.94-5.84 (m,1H), 5.10 (dd, J=1.4, 17.1 Hz, 1H), 5.03 (dd, J=1.1, 10.2 Hz, 1H), 4.51(s, 2H), 3.40 (s, 2H), 3.32 (t, J=7.6 Hz, 2H), 2.99 (s, 6H), 2.66 (q,J=7.5 Hz, 2H), 1.19 (s, 6H); ¹³C NMR (CD₃OD) δ 165.7, 157.6, 140.2,136.3, 135.9, 134.7, 134.5, 125.9, 120.2, 117.9, 115.2, 103.6, 68.8,53.4, 39.6, 32.0, 27.2, 23.7.

EXAMPLE 10 Preparation of3-[2-But-3-enyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(11)

The titled compound (11) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLC:99.4%; t_(R)=0.52 min; LCMS (ESI) m/z: 357 ([M+H]⁺ 1). ¹H NMR (CD₃OD) δ7.94 (d, J=8.7 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.50 (d,J=15.87 Hz, 1H), 6.46 (d, J=15.8 Hz, 1H), 5.96-5.86 (m, 1H), 5.13 (dd,J=1.4, 17.1 Hz, 1H), 5.05 (dd, J=1.1, 10.2 Hz, 1H), 4.93 (t, J=7.9 Hz,2H), 3.62-3.58 (m, 2H), 3.38-3.31 (m, 6H), 2.65 (q, J=7.6 Hz, 2H),1.35-1.32 (m, 6H); ¹³C NMR (CD₃OD) δ 165.8, 157.0, 140.5, 136.6, 135.9,134.6, 134.2, 126.1, 119.5, 117.7, 116.0, 113.3, 50.4, 40.4, 31.7, 26.7,9.1.

EXAMPLE 11 Preparation of3-[2-But-3-ynyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(12)

The titled compound (12) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLC:99.6%; t_(R)=0.37 min; LCMS (ESI) m/z: 355 ([M+H]⁺). ¹H NMR (CD₃OD) δ7.82 (d, J=8.7 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.31 (d,J=15.8 Hz, 1H), 6.31 (d, J=15.8 Hz, 1H), 4.87-4.79 (masked peaks),3.54-3.50 (m, 2H), 3.37 (t, J=7.1 Hz, 2H), 3.24 (q, J=7.2 Hz, 4H), 2.73(dt, J=2.4, 6.9 Hz, 2H), 2.30 (t, J=2.5 Hz, 1H), 1.21 (t, J=7.2 Hz, 6H);¹³C NMR (CD₃OD) δ 165.9, 156.1, 140.9, 138.1, 135.2, 133.4, 125.6,118.8, 117.0, 112.8, 82.4, 72.1, 50.6, 40.2, 26.7, 26.4, 17.3, 9.1.

EXAMPLE 12 Preparation of3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(13)

The titled compound (13) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 96.5%; t_(R)=0.80 min; LCMS (ESI) m/z: 413 ([M+H]⁺).

EXAMPLE 13 Preparation of3-[1-(2-Diethylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(14)

The titled compound (14) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity: 96.4%; t_(R)=1.37 min; LCMS (ESI) m/z: 399 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 1.25 (6H, t), 2.96 (2H, m), 3.31 (6H, m), 3.44 (2H, m), 4.72(2H, m), 6.51 (1H, m), 7.51 (2H, m), 7.65 (1H, m), 7.83 (1H, m), 10.45(1H, bs).

EXAMPLE 14 Preparation of3-[1-(2-Diethylamino-ethyl)-2-ethoxymethyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(15)

The titled compound (15) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity: 98.1%; t_(R)=0.48 min; LCMS (ESI) m/z: 361 ([M+H]⁺).

EXAMPLE 15 Preparation of3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-methyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(16)

The titled compound (16) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity: 99.5%; t_(R)=0.30 min; LCMS (ESI) m/z: 331 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 1.13 (6H, s), 2.78 (2H, m), 2.89 (6H, s), 3.33 (2H, m), 4.42(3H, s), 6.57 (1H, m), 7.57-7.69 (2H, m), 7.95 (2H, m), 9.68 (1H, bs),10.81 (1H, bs).

EXAMPLE 16 Preparation of3-[1-(2-Diethylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(17)

The titled compound (17) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.9%, t_(R)=0.95 min. LCMS (ESI) m/z: 373 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.85 (2H, t, J=8.3 Hz), 7.75 (1H, d, J=8.8 Hz), 7.61(1H, d, J=15.8 Hz), 6.51 (1H, d, J=15.8 Hz), 4.93 (2H, t, J=6.1 Hz),3.54 (2H, t, J=8.1 Hz), 3.31 (4H, qt, J=7.3 Hz), 3.10 (2H, s), 1.27 (6H,t, J=7.3 Hz), 1.06 (9H, s); ¹³C NMR (CD₃OD) δ 163.7, 153.3, 138.3,133.1, 131.9, 124.5, 118.3, 117.1, 113.5, 111.8, 48.1, 39.1, 37.5, 32.9,27.8, 7.1.

EXAMPLE 17 Preparation ofN-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-acrylamide(18)

The titled compound (18) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity: 96.8%; t_(R)=0.72 min. LCMS (ESI) m/z: 399 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 1.18 (6H, d), 2.07 (2H, m), 2.95 (4H, m), 3.27 (3H, m), 4.43(2H, m), 6.52 (1H, m), 7.55 (2H, m), 7.61 (1H, m), 7.84 (1H, m), 8.65(2H, bs).

EXAMPLE 18 Preparation of3-[2-(2,2-Dimethyl-propyl)-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(19)

The titled compound (19) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 98.1%, t_(R)=0.86 min. LCMS (ESI) m/z: 359 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.86 (1H, d, J=8.6 Hz), 7.78 (1H, s), 7.73 (1H, d,J=8.5 Hz), 7.44 (1H, d, J=15.8 Hz), 6.45 (1H, d, J=15.4 Hz), 4.83 (2H,t, J=6.42 Hz), 3.52 (2H, t, J=6.6 Hz), 3.36 (1H, qt, J=6.5 Hz), 3.13(2H, s), 1.26 (6H, d, J=6.2 Hz), 1.04 (9H, s); ¹³C NMR (CD₃OD) δ 161.2,153.4, 138.3, 133.0, 124.4, 113.6, 112.0, 51.1, 41.8, 41.1, 37.3, 33.1,27.8, 17.2.

EXAMPLE 19 Preparation of3-[1-(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(20)

The titled compound (20) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 96.8%, t_(R)=0.94 min. LCMS (ESI) m/z: 400 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.86 (1H, s), 7.80 (1H, d, J=8.7 Hz), 7.76 (1H, d,J=8.6 Hz), 7.62 (1H, d, J=15.8 Hz), 6.52 (1H, d, J=16.0 Hz), 4.96 (2H,t, J=5.2 Hz), 3.84 (2H, m), 3.53 (2H, t, J=8.3 Hz), 3.06 (2H, s), 1.38(12H, d, J=6.5 Hz), 1.05 (9H, s); ¹³C NMR (CD₃OD) δ 160.2, 153.1, 138.2,133.2, 131.9, 124.6, 113.5, 111.8, 54.9, 423.0, 40.5, 37.7, 33.0, 27.8,16.3.

EXAMPLE 20 Preparation of3-[1-(2-Diisopropylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(21)

The titled compound (21) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 95.3%, t_(R)=0.76 min. LCMS (ESI) m/z: 387 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.85 (1H, s), 7.71 (2H, s), 7.66 (1H, d, J=15.8 Hz),6.51 (1H, d, J=15.8 Hz), 4.75 (2H, t, J=7.2 Hz), 3.86 (2H, t, J=6.5 Hz),3.50 (2H, t, J=8.6 Hz), 2.98 (2H, d, J=7.4 Hz), 2.26 (1H, m) 1.41 (12H,d, J=6.3 Hz), 1.06 (6H, d, J=6.6 Hz).

EXAMPLE 21 Preparation of3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(22)

The titled compound (22) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.9%; t_(R)=1.24 min; LCMS (ESI) m/z: 399 ([M+H]⁺).¹H NMR (CD₃OD) δ 8.22 (d, J=8.7 Hz, 1H), 8.11 (s, 1H), 7.96 (d, J=8.6Hz, 1H), 7.81 (d, J=15.8 Hz, 1H), 6.68 (d, J=15.8 Hz, 1H), 5.69-5.59 (m,2H), 4.79 (s, 2H), 3.66 (s, 2H), 3.55 (t, J=7.3 Hz, 2H), 3.24 (s, 6H),2.91 (q, J=6.8 Hz, 2H), 2.21-2.11 (m, 2H), 1.44 (s, 6H), 1.02 (t, J=7.5Hz, 3H); ¹³C NMR (CD₃OD) δ 165.7, 157.9, 140.2, 135.8, 134.6, 134.5,126.1, 125.9, 120.1, 115.2, 114.6, 68.7, 533, 47.9, 39.6, 27.6, 25.9,23.7, 21.4, 14.4.

EXAMPLE 22 Preparation of3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(23)

The titled compound (23) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 98.6%; t_(R)=1.61 min; LCMS (ESI) m/z: 429 ([M+H]⁺).¹H NMR (CD₃OD) δ 8.19 (d, J=8.8 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J=8.8Hz, 1H), 7.76 (d, J=15.7 Hz, 1H), 6.75 (d, J=15.8 Hz, 1H), 4.79 (s, 2H),3.62 (s, 2H), 3.35-3.29 (m, 1H), 3.23 (s, 6H), 2.52 (brs, 2H), 1.50-1.45(m, 2H), 1.36 (d, J=3.8 Hz, 6H), 1.12 (d, J=5.5 Hz, 3H), 1.02 (s, 6H);¹³C NMR (CD₃OD) δ 165.6, 157.4, 139.9, 135.2, 135.1, 132.9, 126.4,120.6, 115.7, 114.6, 68.6, 53.3, 51.4, 47.9, 39.7, 36.3, 31.9, 31.3,30.2, 23.8, 22.3.

EXAMPLE 23 Preparation of3-[2-Cyclohexyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(24)

The titled compound (24) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.9%; t_(R)=0.96 min; LCMS (ESI) m/z: 399 ([M+H]⁺).¹H NMR (CD₃OD): δ 8.21 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.95 (d, J=8.8Hz, 1H), 7.83 (d, J=15.8 Hz, 1H), 6.76 (d, J=15.8 Hz, 1H), 4.79 (s, 2H),3.65 (s, 2H), 3.60-3.51 (m, 1H), 3.22 (s, 6H), 3.29-3.26 (m, 2H),2.12-2.09 (m, 2H), 2.03-1.92 (m, 3H), 1.78-1.59 (m, 3H), 1.41 (s, 6H);¹³C NMR (CD₃OD) δ 165.7, 161.3, 140.1, 135.4, 134.8, 134.0, 126.1,120.3, 119.6, 116.7, 115.5, 114.9, 68.7, 53.1, 47.9, 39.2, 37.0, 32.4,26.5, 26.3, 23.6.

EXAMPLE 24 Preparation of3-[2-Bicyclo[2.2.1]hept-5-en-2-yl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(25)

The titled compound (25) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.9%; t_(R)=0.91 min; LCMS (ESI) m/z: 409 ([M+H]⁺).

EXAMPLE 25 Preparation of3-[1-(2-Diethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(26)

The titled compound (26) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLC:99.9%; t_(R)=1.14 min; LCMS (ESI) m/z: 385 ([M+H]⁺). ¹H NMR (CD₃OD) δ7.95 (d, J=8.6 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.52 (d,J=15.8 Hz, 1H), 6.50 (d, J=15.8 Hz, 1H), 5.57-5.44 (m, 2H), 3.72-3.68(m, 2H), 3.44 (q, J=7.2 Hz, 4H), 3.35-3.30 (masked peaks), 2.73 (q,J=7.1 Hz, 2H), 2.07-1.99 (m, 2H), 1.41 (t, J=7.2 Hz, 6H), 0.88 (t, J=7.5Hz, 3H); ¹³C NMR (CD₃OD) δ 165.6, 157.2, 140.2, 135.9, 134.8, 134.6,134.2, 126.4, 126.1, 119.8, 115.6, 113.5, 50.4, 40.5, 26.9, 25.4, 21.4,14.4, 8.9.

EXAMPLE 26 Preparation of3-[1-(2-Diisopropylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(27)

The titled compound (27) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLC:99.9%; t_(R)=1.22 min; LCMS (ESI) m/z: 413 ([M+H]⁺). ¹H NMR (CD₃OD) δ7.94-7.89 (m, 2H), 7.78 (d, J=8.7 Hz, 1H), 7.53 (d, J=15.8 Hz, 1H), 6.50(d, J=15.8 Hz, 1H), 5.63-5.44 (m, 2H), 3.99-3.91 (m, 2H), 3.69-3.64 (m,2H), 3.36-3.26 (masked peaks), 2.72 (q, J=7.2 Hz, 2H), 2.08-2.01 (m,2H), 1.50 (d, J=6.5 Hz, 12H), 0.89 (t, J=7.5 Hz, 3H); ¹³C NMR (CD₃OD) δ165.6, 157.0, 140.2, 135.9, 135.4, 134.5, 134.3, 126.6, 126.3, 126.2,119.8, 115.8, 113.3, 56.9, 45.3, 41.9, 27.2, 25.5, 21.4, 18.2, 14.4.

EXAMPLE 27 Preparation of3-[2-Hex-3-enyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(28)

The titled compound (28) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.9%; t_(R)=1.12 min; LCMS (ESI) m/z: 371 ([M+H]⁺).¹H NMR (CD₃OD) δ 8.00 (d, J=9.1 Hz, 1H), 7.77-7.75 (m, 2H), 7.17 (d,J=15.7 Hz, 1H), 6.34 (d, J=15.7 Hz, 1H), 5.57-5.42 (m, 2H), 4.92 (t,J=5.9 Hz, 2H), 3.72 (t, J=5.7 Hz, 2H), 3.54-3.48 (m, 1H), 3.39 (t, J=7.5Hz, 2H), 2.72 (q, J=7.3 Hz, 2H), 2.06-1.99 (m, 2H), 1.39 (d, J=6.5 Hz,6H), 0.87 (t, J=7.5 Hz, 3H).

EXAMPLE 28 Preparation of3-[1-(2-Ethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(29)

The titled compound (29) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.9%; t_(R)=1.23 min; LCMS (ESI) m/z: 385 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.94 (d, J=8.6 Hz, 1H), 7.89 (s, 1H), 7.77 (d, J=8.4Hz, 1H), 7.56 (d, J=15.8 Hz, 1H), 6.55 (d, J=15.7 Hz, 1H), 5.57-5.42 (m,2H), 4.62 (t, J=7.5 Hz, 2H), 3.42-3.33 (m, 1H), 3.32-3.30 (maskedpeaks), 3.28-3.24 (m, 2H), 2.71 (q, J=7.2 Hz, 2H), 2.33 (brs, 2H),2.03-1.94 (m, 2H), 1.36 (d, J=6.5 Hz, 6H), 0.84 (t, J=7.5 Hz, 3H); ¹³CNMR (CD₃OD) δ 165.6, 156.3, 139.9, 136.8, 136.2, 135.2, 133.8, 132.8,126.7, 125.8, 120.4, 114.6, 114.1, 52.2, 43.5, 42.9, 27.2, 26.5, 25.5,21.4, 19.2, 14.4.

EXAMPLE 29 Preparation of3-[2-Hex-3-enyl-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(30)

The titled compound (30) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.9%; t_(R)=1.04 min; LCMS (ESI) m/z: 357 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.93 (d, J=8.4 Hz, 1H), 7.77-7.73 (m, 2H), 7.23 (d,J=15.7 Hz, 1H), 6.34 (d, J=15.7 Hz, 1H), 5.57-5.42 (m, 2H), 4.87 (maskedpeaks), 3.68 (brs, 2H), 3.35-3.30 (masked peaks), 3.22-3.17 (m, 2H),2.72 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H), 0.88 (t, J=7.6 Hz, 3H);¹³C NMR (CD₃OD) δ 165.6, 157.3, 140.5, 135.8, 134.9, 134.6, 134.2,126.2, 126.1, 118.7, 115.9, 113.7, 113.6, 46.5, 45.0, 42.7, 26.4, 25.4,21.4, 14.4, 11.4.

EXAMPLE 30 Preparation of3-[1-(2-Diethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(31)

The titled compound (31) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 100%, t_(R)=1.31 min. LC-MS m/z: 387 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.88 (3H, t, J=7.0 Hz), 1.26 (6H, t, J=7.2 Hz), 1.34 (4H,m), 1.44 (2H, m), 1.85 (2H, m), 3.12 (2H, t, J=7.7 Hz), 3.31 (4H, m),3.52 (2H, t, J=7.7 Hz), 4.81 (2H, t, J=7.7 Hz), 6.59 (1H, d, J=15.8 Hz),7.63 (1H, d, J=15.8 Hz), 7.73 (1H, d, J=8.8 Hz), 7.93 (1H, d, J=8.8 Hz),7.94 (1H, s).

EXAMPLE 31 Preparation of3-[1-(3-isopropylamino-propyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(32)

The titled compound (32) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: HPLC: 97.5%, t_(R)=1.68 min. LC-MS m/z: 415 ([M+H]⁺).¹H NMR (DMSO-d₆) δ 0.89 (9H, s), 0.98 (3H, d, J=6.6 Hz), 1.23 (6H, d,J=6.5 Hz), 2.08-2.29 (4H, m), 2.27 (1H, m), 2.98-3.12 (4H, m), 3.29 (1H,m), 4.53 (2H, t, J=7.4 Hz), 6.60 (1H, d, J=15.8 Hz), 7.65 (1H, d, J=15.8Hz), 7.75 (1H, d, J=9.0 Hz), 7.96 (1H, d, J=9.0 Hz), 7.98 (1H, s), 8.75(2H, bs).

EXAMPLE 32 Preparation of3-[2-(2,2-Dimethyl-propyl)-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(33)

The titled compound (33) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99%, t_(R)=1.01 min. LC-MS m/z: 375 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.98 (9H, s), 1.24 (6H, bs), 2.17 (2H, bs), 3.14 (4H, m),3.28 (1H, bs), 4.53 (2H, bs), 6.65 (1H, d, J=15.5 Hz), 7.65 (1H, d,J=15.5 Hz), 7.81 (1H, d, J=7.4 Hz), 8.02 (1H, s), 8.03 (1H, d, J=7.4Hz), 8.85 (2H, bs).

EXAMPLE 33 Preparation of3-[1-(2-Diisopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(34)

The titled compound (34) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLC:97.5%; t_(R)=0.93 min. LCMS (ESI) m/z: 427 ([M+H]⁺). ¹H NMR (DMSO-d₆)δ1.35 (12H, m), 2.94 (2H, m), 3.24 (2H, m), 3.45 (2H, t), 3.80 (2H, m),4.68 (2H, t), 6.48 (1H, m), 7.55 (3H, m), 7.85 (1H, m), 9.48 (1H, bs).

EXAMPLE 34 Preparation ofN-Hydroxy-3-[2-isobutyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-acrylamide(35)

The titled compound (35) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 98.3%, t_(R)=0.51 min. LCMS (ESI) m/z: 345 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.78 (1H, d, J=8.7 Hz), 7.76 (1H, s), 7.68 (1H, d,J=8.6 Hz), 7.46 (1H, d, J=15.8 Hz), 6.42 (1H, d, J=15.9 Hz), 4.70 (2H,t, J=7.4 Hz), 3.48 (2H, t, J=6.9 Hz), 3.37 (1H, m), 3.01 (2H, d, J=7.4Hz), 2.21 (1H, m), 1.27 (6H, d, J=6.5 Hz), 1.00 (6H, d, J=6.6 Hz); ¹³CNMR (CD₃OD) δ 160.3, 155.3, 138.5, 134.1, 131.5, 124.2, 113.9, 111.4,51.1, 42.0, 40.3, 33.4, 27.3, 20.6, 17.2.

EXAMPLE 35 Preparation of3-[2-(2,2-Dimethyl-propyl)-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(36)

The titled compound (36) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. Yield:74%. HPLC purity at 254 nm: 99.9%, t_(R)=0.71 min. LCMS (ESI) m/z: 345([M+H]⁺). ¹H NMR (CD₃OD) δ 7.81 (1H, d, J=8.6 Hz), 7.75 (1H, s), 7.69(1H, d, J=8.5 Hz), 7.36 (1H, d, J=15.7 Hz), 6.40 (1H, d, J=15.3 Hz),4.81 (2H, t, J=6.4 Hz), 3.51 (2H, t, J=6.3 Hz), 3.10 (2H, s), 3.06 (2H,qt, J=7.3 Hz), 1.23 (3H, t, J=7.2 Hz), 1.04 (9H, s); ¹³C NMR (CD₃OD) δ161.0, 153.3, 138.5, 132.7, 132.2, 124.2, 117.5, 113.9, 111.9, 44.2,43.0, 41.0, 37.4, 33.0, 27.9, 9.5.

EXAMPLE 36 Preparation of3-[1-(2-Ethylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(37)

The titled compound (37) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.9%, t_(R)=0.40 min. LCMS (ESI) m/z: 331 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.81 (1H, d, J=8.6 Hz), 7.73 (1H, s), 7.67 (1H, d,J=8.2 Hz), 7.34 (1H, d, J=15.7 Hz), 6.36 (1H, d, J=15.7 Hz), 4.74 (2H,t, J=6.7 Hz), 3.54 (2H, t, J=6.5 Hz), 3.10 (2H, d, J=7.4 Hz), 3.06 (2H,d, J=9.5 Hz), 2.21 (1H, m), 1.23 (3H, t, J=7.3 Hz), 1.04 (6H, d, J=6.6Hz); ¹³C NMR (CD₃OD) δ 163.7, 161.1, 154.8, 138.6, 133.2, 132.6, 132.4,124.2, 117.2, 113.9, 111.6, 44.4, 43.0, 40.5, 33.4, 27.3, 20.6, 9.5.

EXAMPLE 37 Preparation of3-[1-(2-Diisopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(38)

The titled compound (38) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLC:99.0%; t_(R)=1.62 min; LCMS (ESI) m/z: 443 ([M+H]⁺). ¹H NMR (CD₃OD) δ7.96-7.94 (m, 2H), 7.82 (d, J=8.7 Hz, 1H), 7.55 (d, J=15.8 Hz, 1H), 6.54(d, J=15.8 Hz, 1H), 5.13-5.06 (masked peaks), 4.01-3.92 (m, 2H),3.71-3.67 (m, 2H), 3.33-3.24 (masked peaks), 3.18-3.12 (m, 1H),2.38-2.36 (m, 1H), 1.52 (s, 6H), 1.51 (s, 6H), 1.41-1.40 (m, 2H), 1.09(d, J=6.6 Hz, 3H), 0.94 (s, 9H); ¹³C NMR (CD₃OD) δ 165.5, 156.5, 140.1,134.8, 134.7, 134.0, 126.5, 120.0, 114.6, 113.6, 56.9, 51.7, 45.2, 42.0,35.9, 31.9, 30.6, 30.2, 22.6, 18.3.

EXAMPLE 38 Preparation ofN-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-acrylamide(39)

The titled compound (39) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 97.9%; t_(R)=1.49 min; LCMS (ESI) m/z: 401 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.98 (d, J=8.7 Hz, 1H), 7.79-7.76 (m, 2H), 7.24 (d,J=15.7 Hz, 1H), 6.39 (d, J=15.7 Hz, 1H), 4.97-4.89 (masked peaks),3.70-3.66 (m, 2H), 3.53-3.47 (m, 1H), 3.34-3.28 (masked peaks),3.22-3.15 (m, 1H), 2.31-2.29 (m, 1H), 1.39-1.38 (m, 9H), 1.07 (d, J=6.6Hz, 3H), 0.9 (s, 9H); ¹³C NMR (CD₃OD) δ 165.5, 156.9, 140.5, 134.7,134.4, 126.3, 118.9, 115.9, 113.8, 53.2, 51.5, 44.2, 42.8, 35.7, 31.9,30.9, 30.2, 29.6, 19.1, 18.8.

EXAMPLE 39 Preparation of3-[1-(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(40)

The titled compound (40) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 100.0%; t_(R)=1.57 min; LCMS (ESI) m/z: 387 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.96 (d, J=8.6 Hz, 1H), 7.79 (s, 1H), 7.78-7.75 (d,J=8.7 Hz, 1H), 7.23 (d, J=15.7 Hz, 1H), 6.37 (d, J=15.7 Hz, 1H),4.96-4.89 (masked peaks), 3.70-3.68 (m, 2H), 3.36-3.28 (masked peaks),3.26-3.14 (m, 3H), 2.31-2.30 (m, 1H), 1.40-1.32 (m, 5H), 1.07 (d, J=6.6Hz, 3H), 0.92 (s, 9H); ¹³C NMR (CD₃OD) δ 165.6, 156.9, 140.6, 134.9,134.5, 134.2, 126.2, 118.7, 116.0, 113.7, 51.6, 46.5, 45.0, 42.7, 35.8,31.9, 30.8, 30.2, 22.6, 11.4.

EXAMPLE 40 Preparation of3-[1-(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(41)

The titled compound (41) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 85.6%, t_(R)=1.55 min. LC-MS m/z: 415 ([M+H]⁺). ¹H NMR(CD₃OD) δ 7.91 (d, 2H, J=6.0 Hz), 7.80 (br, d, 1H, J=8.9 Hz), 7.68 (d,2H, J=15.8 Hz), 6.58 (d, 1H, J=15.8 Hz), 4.96 (br, q, 2H), 3.64 (br, q,2H), 3.43 (q, 4H, J=7.3 Hz), 1.40 (t, 8H), 1.09 (br, d, 4H, J=6.6 Hz),0.94 (br, s, 10H); ¹³C NMR (CD₃OD) δ 156.8, 140.4, 135.8, 134.4, 134.3,126.1, 115.8, 113.2, 119.7, 119.2, 51.6, 50.3, 40.3, 35.8, 31.9, 22.6,9.0.

EXAMPLE 41 Preparation of3-[1-(2-Diethylamino-ethyl)-2-propyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(42)

The titled compound (42) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.0%, t_(R)=0.68 min. LC-MS (ESI) m/z: 345 ([M+H]⁺).¹H NMR (CD₃OD) δ 8.15 (d, 2H, J=8.7 Hz), 7.68 (d, 1H, J=15.8 Hz), 6.63(d, 1H, J=15.8 Hz), 5.08 (br, t, 2H), 3.70 (br, t, 2H), 3.44 (br, m,4H), 3.35 (t, 2H), 2.03 (br, m, 2H), 1.44 (t, 6H, J=7.2 Hz), 1.20 (t,3H); ¹³C NMR (CD₃OD) δ 165.5, 157.4, 139.8, 135.5, 133.5, 132.3, 120.7,120.7, 114.5, 114.3, 40.8, 28.5, 21.0, 13.9, 9.1.

EXAMPLE 42 Preparation of3-[1-(2-Diethylamino-ethyl)-2-(2-methylsulfanyl-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(45)

The titled compound (45) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. Yield:17 mg (in two steps) as TFA salt. HPLC purity at 254 nm: 80%, t_(R)=0.50min. LCMS (ESI) m/z: 377 ([M+H]⁺). ¹H NMR (CD₃OD) δ 7.79 (1H, s), 7.77(1H, d), 7.66 (1H, d, J=8.6 Hz), 7.54 (1H, d, J=15.8 Hz), 6.44 (1H, d,J=15.8 Hz), 4.83 (2H, masked by DHO, identified by COSY), 3.57 (2H, m),3.41 (2H, t, J=7.1 Hz), 3.32 (4H), 3.01 (2H, t, J=7.1 Hz), 2.89 (3H, s),1.30˜1.25 (9H, overlapped t).

EXAMPLE 43 Preparation of3-[2-Butyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(46)

The titled compound (46) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 98.4%; t_(R)=1.56 min. LCMS m/z: 345 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.95 (3H, t), 1.22 (6H, m), 1.42 (2H, m), 1.80 (2H, m), 3.13(2H, m), 3.41 (3H, t), 4.69 (2H, t), 6.58 (1H, m), 7.56 (1H, m), 7.73(1H, m), 7.90 (2H, m), 9.14 (2H, bs).

Preparation of the Freebase of the Titled Compound:

To a pre-stirred solution of the methyl ester (1 eq) in dried methanol,NH₂OH.HCl (12 eq.) was added. The mixture was stirred in ice-water bathfor about 10 min, followed by adding sodium methoxide solution (20 eq.).HPLC showed the reaction completed after 20 min, less than 1% of theacid was observed.

The above crude was treated with 1M of HCl until all the precipitate wasdissolved (pH around 1-2). The pH value was carefully adjusted to around7-8 using NaOH or NaHCO₃, the precipitate which was formed was collectedby filtration. The solid was washed with water once. The above solid wassuspended in methanol and water again and was treated with 6N HCl untilall dissolved, the pH value was carefully adjusted to around 7-8 usingNaOH and NaHCO₃. The precipitate, which was formed, was again collectedby filtration; the freebase compound was obtained by drying in vacuo,the yield was around 80%-85%.

Preparation of the Hydrochloric Acid Salt of the Titled Compound:

The above freebase compound was suspended in methanol and water and wastreated with 6N HCl (2.8 eq.). The solution became clear. After removingthe methanol on a Rotary Evaporator, the hydrochloric acid salt wasobtained by freeze-drying. It was further recrystallized from methanol(HPLC purity at 254 nm: >99%).

EXAMPLE 44 Preparation of3-[2-Butyl-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(47)

The titled compound (47) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 98.2%; t_(R)=1.72 min. LCMS (ESI) m/z: 359 ([MH]⁺). ¹HNMR (DMSO-d₆) δ 0.95 (3H, t), 1.22 (6H, m), 1.45 (2H, m), 1.82 (2H, m),2.14 (2H, m), 3.17 (4H, m), 3.28 (1H, m), 4.52 (2H, t), 6.62 (1H, m),7.57 (1H, m), 7.72 (1H, m), 7.89 (2H, m), 8.80 (2H, bs).

EXAMPLE 45 Preparation of3-[1-(1-Benzyl-piperidin-4-yl)-2-butyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(48)

The titled compound (48) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 96.7%, t_(R)=1.35 min. LC-MS m/z: 433 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.94 (3H, s), 1.41 (2H, m), 1.77 (2H, m), 2.19 (2H, m),2.99-3.10 (2H, m), 3.24 (4H, m), 3.68 (2H, m), 4.38 (2H, s), 5.01 (1H,m), 6.65 (1H, d, J=15.8 Hz), 7.47-7.49 (3H, m), 7.61 (1H, d, J=15.8 Hz),7.69 (3H, m), 7.97 (1H, s), 8.60 (1H, d, J=8.8 Hz), 10.35 (2H, s), 11.95(1H, s).

EXAMPLE 46 Preparation of3-[2-Butyl-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(44)

The titled compound (44) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 98%; LC-MS m/z: 331 ([M+H]⁺). ¹H NMR (DMSO-d₆) δ 10.88(br s, 1H), 9.12 (br s, 2H), 7.93 (s, 1H), 7.87 (d, 1H, J=8.4 Hz), 7.71(d, 1H, J=8.3 Hz), 7.62 (d, 1H, J=15.7 Hz), 6.59 (d, 1H, J=15.6 Hz),4.67 (t-like, 2H), 3.42 (br s, 2H), 3.08 (q, 2H, J=7.7 Hz, Pr—CH₂), 3.05(br s, 2H), 1.81 (m, 2H), 1.45 (m, 2H), 1.18 (t, 3H, J=7.1 Hz), 0.95 (t,3H, J=7.0 Hz); ¹³C NMR (DMSO-d₆) δ 162.6, 156.2, 138.0, 135.0, 133.5,131.6, 123.5, 119.2, 114.8, 112.1, 44.5, 42.4, 40.6, 28.2, 25.2, 21.7,13.5, 10.8.

EXAMPLE 47 Preparation of3-[2-But-3-enyl-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(49)

The titled compound (49) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLC:99.0%; t_(R)=1.61 min; LCMS m/z: 329 ([M+H]⁺). ¹H NMR (CD₃OD) δ 7.85 (d,J=8.5 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.38 (d, J=15.7 Hz,1H), 6.40 (d, J=15.5 Hz, 1H), 6.02-5.92 (m, 1H), 5.19 (dd, J=17.1, 1.3Hz, 1H), 5.12 (dd, J=10.2, 0.9 Hz, 1H), 4.80 (t, J=6.4 Hz, 2H), 3.62 (t,J=6.2 Hz, 2H), 3.22-3.16 (m, 2H), 2.71 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2Hz, 3H); ¹³C NMR (CD₃OD) δ 178.3, 157.1, 140.7, 136.5, 133.9, 125.9,118.8, 117.6, 116.2, 113.2, 101.5, 67.6, 46.4, 44.9, 42.4, 31.6, 26.7,20.7, 11.4.

EXAMPLE 48 Preparation of3-[2-Hexyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(50)

The titled compound (50) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 94.4%, t_(R)=1.32 min. LCMS (ESI) m/z: 373 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.80 (1H, d, J=8.5 Hz), 7.74 (1H, s), 7.64 (1H, d,J=9.0 Hz), 7.50 (1H, d, J=13.6 Hz), 6.42 (1H, d, J=15.8 Hz), 4.65 (2H,d, J=6.6 Hz), 3.48 (2H, d, J=6.6 Hz), 3.38 (1H, qt, J=6.5 Hz), 3.13 (2H,t, J=5.9 Hz) 1.82 (2H, t, J=6.7 Hz), 1.44 (2H, t, J=7.0 Hz) 1.29 (7H, m)0.84 (6H, d, J=7.0 Hz).

EXAMPLE 49 Preparation of3-[1-(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(51)

The titled compound (51) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 100%, t_(R)=1.49 min. LC-MS m/z: 331 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.85 (9H, s), 1.03 (2H, d, J=6.4 Hz), 1.34 (2H, m), 2.27(1H, m), 3.00 (6H, s), 3.24-3.27 (4H, m), 4.79 (3H, m), 6.53 (1H, d,J=15.72 Hz), 7.62 (1H, d, J=15.7 Hz), 7.75 (1H, d, J=8.4 Hz), 7.86 (1H,s), 7.87 (1H, d, J=8.4 Hz).

EXAMPLE 50 Preparation of3-[1-(2-Ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(52)

The titled compound (52) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. Themodified or detailed procedures were described as below.

Step 3:

To a stirred solution of3-[4-(2-ethylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester(8.174 g, 27.87 mmol) and heptaldehyde (4.85 g, 42.47 mmol, 1.52 eq) inAcOH and MeOH (1:9 v/v, 300 mL) was added SnCl₂.2H₂O (31.45 g, 139.4mmol, 5 eq) in portions. The resulting mixture was heated to 40° C. withstirring. The progress of the reaction was monitor by LC/MS. When thereaction was completed, solvent was removed under reduced pressure below40° C. The resultant residue was diluted with EtOAc (50 mL) thenbasified (pH>10) with saturated aqueous Na₂CO₃ and extracted withdichloromethane (×3). Filtration may be needed to remove the whiteprecipitates or suspension derived from Tin in order to get clearlyseparated layers. The organic extracts were combined, dried (Na₂SO₄),filtered, and evaporated to dryness. The resulting oily residue waspurified by flash column chromatography (silica, φ67×65 mm, solventMeOH/DCM gradient from 0 to 10%).3-[1-(2-ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-acrylic acidmethyl ester was obtained as yellow solid (4.445 g, 44.6%). HPLC purityat 254 nm: 98.8%, t_(R)=1.71 min. LCMS (ESI) m/z: 358 ([M+H]⁺). ¹H NMR(CDCl₃) δ 7.88 (1H, d, J=1.2 Hz), 7.83 (1H, d, J=16.0 Hz), 7.43 (1H, dd,J=8.4, 1.4 Hz), 7.33 (1H, d, J=8.4 Hz), 6.43 (1H, d, J=15.9 Hz), 4.22(2H, t, J=6.6 Hz), 3.80 (3H, s), 3.01 (2H, t, J=6.6 Hz), 2.89 (2H, t,J=7.9 Hz), 2.65 (2H, q, J=7.1 Hz), 1.91 (2H, pentet, J=7.8 Hz), 1.46(2H, m), 1.35 (4H, m), 1.07 (3H, t, J=7.1 Hz), 0.90 (3H, t, J=7.0 Hz).The solid could be recrystallized from Hexanes-ether to give a white orpale yellow solid with HPLC purity at 254 nm: 99.2%.

In another experiment starting with 2.725 g of3-[4-(2-ethylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methylester, the titled compound was obtained in 52.8% yield (1.753 g).

Step 4:

To a solution of3-[1-(2-ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-acrylic acidmethyl ester (4.428 g, 12.39 mmol) and NH₂OH.HCl (8.66 g, 124.7 mmol) indry MeOH (50 mL) which was stirred and cooled in a dry-ice acetone bath,added NaOMe solution in MeOH (25%, 4.37 M, 55 mL, 240 mmol). Thereaction mixture was then stirred at room temperature. The progress ofreaction was monitored by LC/MS (usually reaction completed within 30˜90min) and quenched by adding 6N HCl (40 mL). The mixture (HPLC purity at254 nm=94.6%) was added Milli-Q water, adjusted pH ˜8 by 1N NaOH andevaporated to remove the organic solvent. The resultant residue waswashed with Milli-Q water (×3) and re-dissolved in MeOH-DCM, thesolution was filtered and diluted with Milli-Q water. The suspension wasevaporated to remove the organic solvent and the resultant residue waswashed with Milli-Q water (×2). The free base of the titled compound wasobtained (HPLC purity at 254 nm=98%). The free base could berecrystallized from MeOH-Ethyl acetate to give a white or pale yellowsolid.

Step 5: Hydrochloric Acid Salt Formation.

The above freebase was dissolved in MeOH and excess 6N HCl (final pH<2)and the clear solution was evaporated to dryness and then diluted withMeOH, co-evaporated with PhMe (×1) and EtOAc (×2). The solid wasrecrystallized from MeOH-EtOAc to give a white or pale yellow solid(3.298 g, 61.7%). HPLC purity at 254 nm: 98.4˜99.6%, t_(R)=1.23 min.LCMS (ESI) m/z: 359 ([M+H]⁺). ¹H NMR (CD₃OD) δ 9.33 (residual NH), 8.03(1H, d, J=8.3 Hz), 7.77 (1H, s), 7.73 (1H, d, J=8.2 Hz), 7.16 (1H, d,J=15.7 Hz), 6.34 (1H, d, J=15.7 Hz), 4.88 (2H, overlapped with DHO,identified by COSY), 3.63 (2H, br t like), 3.32 (2H, d, J=7.9 Hz), 3.15(2H, q, J=7.1), 1.94 (2H, pentet, J=7.1), 1.53 (2H, pentet, J=6.7 Hz),1.42-1.31 (4H, m), 1.33 (3H, t, J=7.1 Hz), 0.88 (3H, t, J=7.0 Hz); ¹³CNMR (CD₃OD) δ 163.4, 155.8, 138.1, 133.0, 132.0, 130.3, 125.1, 117.4,112.8, 112.5, 44.5, 43.2, 41.1, 30.5, 28.0, 25.3, 25.2, 21.6, 12.4, 9.6.Anal. (C₂₀H₃₀N₄O₂.2HCl) Cl: calcd, 16.44. found, 16.00.

EXAMPLE 51 Preparation ofN-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-acrylamide(53)

The titled compound (53) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLC:98.1%; t_(R)=0.63 min. LC-MS m/z: 385 ([M+H]⁺).

EXAMPLE 52 Preparation of3-[1-(2-Dimethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(54)

The titled compound (54) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 99.9%, t_(R)=0.96 min. LCMS (ESI) m/z: 357 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.87 (1H, d, J=8.6 Hz), 7.80 (1H, d, J=8.8 Hz), 7.72(1H, d, J=8.3 Hz), 7.49 (1H, d, J=15.8 Hz), 6.44 (1H, d, J=15.8 Hz),5.44 (1H, m), 5.38 (1H, m), 4.84 (2H, t, J=6.1 Hz), 3.61 (2H, t, J=7.7Hz), 3.20 (2H, t, J=4.2 Hz) 2.97 (6H, s), 2.61 (4H, qt, J=7.1 Hz), 1.93(2H, qn, J=7.7 Hz), 0.78 (3H, t, J=7.5 Hz); ¹³C NMR (CD₃OD) δ 163.6,160.0, 155.1, 138.1, 134.1, 133.1, 131.9, 131.6, 124.7, 123.9, 118.2,117.2, 114.3, 113.1, 111.8, 53.2, 42.1, 38.8, 24.8, 23.3, 19.4, 12.4.

EXAMPLE 53 Preparation of3-[1-(2-Amino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(55)

Step 1:

To a stirred solution of3-[4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-phenyl]-acrylicacid methyl ester (IIIa1, 65.2 mg, 0.178 mmol) and3,5,5-trimethylhexanal (45 μL, 0.26 mmol) in a mixed solvent ofAcOH-MeOH (1:9 v/v, 2 mL) and DCM (1 mL) was added SnCl₂.2H₂O (184 mg,0.815 mmol). The resulting mixture was heated to 40° C. with stirringovernight. The solvent was removed under reduced pressure and theresultant residue was added saturated aqueous Na₂CO₃ and extracted withEtOAc (×3). The extracts gave the crude (VIa1-1, 91 mg) with HPLC purityat 254 nm: 49.3%, t_(R)=3.02 min and 7.9%, t_(R)=1.97 min (de-Bocproduct). LCMS (ESI) m/z: 458 ([M+H]⁺) and 358 ([M+H]⁺, de-Boc product).

Step 2:

The above crude (VIa1-1) was dissolved in MeOH (4 mL) and 6N HCl (1 mL)and heated at 70° C. for 30 min. The solution was evaporated to drynessand co-evaporated with PhMe (×2) and MeOH (×1). The residue (crudeVIa-1, 81.9 mg) was spilt to two parts (43.4 mg, equal to 0.0945 mmol ofIIIa1, and 38.5 mg equal to 0.0839 mmol of IIIa1).

Step 3:

The titled compound (55) was prepared according to the Step 4 describedin Example 1, by using crude (VIa-1, 38.5 mg). VIIa-1 was obtained asTFA salt (2.3 mg, 4.7% from IIIa1). HPLC purity at 254 nm: 92.7%,t_(R)=1.46 min. LCMS (ESI) m/z: 359 ([M+H]⁺). ¹H NMR (CD₃OD) δ 7.81 (1H,s), 7.70 (1H, d, J=8.6 Hz), 7.65 (1H, d, J=8.4 Hz), 7.59 (1H, d, J=15.8Hz), 6.47 (1H, brd, J=14.6 Hz), 4.63 (2H, t, J=5.4 Hz), 3.38 (2H, t,J=6.5 Hz), 3.02 (1H, dd, J=15.5, 6.5 Hz), 2.90 (1H, dd, J=15.3, 8.6 Hz),2.20 (1H, brs or m), 1.33 (1H, dd, J=14.1, 3.4 Hz), 1.25 (1H, dd,J=14.0, 6.6 Hz), 0.98 (3H, d, J=6.2 Hz), 0.83 (9H, s).

EXAMPLE 54 Preparation of3-[1-(2-Amino-ethyl)-2-(2-methoxy-nonyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(56)

The titled compound (56) was prepared according to the proceduresdescribed in Example 53, by using appropriate starting materials. HPLCpurity at 254 nm: 91.8%, t_(R)=1.93 min. LCMS (ESI) m/z: 403 ([M+H]⁺).¹H NMR (CD₃OD) δ some identified peaks: 7.81 (1H, s), 7.70˜7.58 (3H, m),6.46 (1H, br d, J=14.4 Hz), 4.62 (2H, m), 3.69 (1H, br s or m), 3.38(2H, t, J=7.3 Hz), 1.67 (1H, m), 1.56 (1H, m), 1.50-1.20 (10H, m), 0.82(3H, t, J=6.2 Hz).

EXAMPLE 55 Preparation of3-[2-Butyl-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(57)

The titled compound (57) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 100%, t_(R)=0.42 min. LC-MS m/z: 331 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.97 (3H, t, J=7.3 Hz), 1.49 (3H, m), 1.83 (2H, m), 3.09(2H, t, J=7.72 Hz), 3.54 (2H, t, J=7.6 Hz), 4.74 (2H, t, J=7.6 Hz), 6.57(1H, d, J=15.7 Hz), 7.62 (1H, d, J=15.7 Hz), 7.71 (1H, d, J=8.6 Hz),7.93 (1H, d, J=8.6 Hz), 7.97 (1H, s), 10.68 (2H, bs).

EXAMPLE 56 Preparation of3-[2-Hexyl-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(58)

The titled compound (58) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 100%, t_(R)=0.42 min. LC-MS m/z: 359 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.89 (3H, t, J=6.9 Hz), 1.28-1.54 (6H, m), 1.85 (2H, m),2.92 (6H, s), 3.09 (2H, t, J=7.6 Hz), 3.51 (2H, t, J=7.8 Hz), 4.76 (2H,t, J=7.8 Hz), 6.57 (1H, d, J=15.8 Hz), 7.63 (1H, d, J=15.8 Hz), 7.70(1H, d, J=8.6 Hz), 7.90 (1H, d, J=8.6 Hz), 7.91 (1H, s), 10.68 (2H, bs).

EXAMPLE 57 Preparation of3-{1-(2-Diethylamino-ethyl)-2-[2-(2,2-dimethyl-propionylamino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(61)

The titled compound (61) was prepared according to the proceduresdescribed below, Steps 1 & 2 were performed as in Scheme I:

Step 3:

To a pre-stirred solution of3-[4-(2-diethylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methylester (61-1, 280 mg, 1.0 mmol) in glacial acetic acid (5 mL), tinchloride was added (1.18 g, 10.0 mmol). The resulting solution washeated to 45° C. for 17 hours and then cooled to room temperature. Thesolvent was removed under vacuum. Water (20 mL) and dichloromethane (20mL) was added to the residue and stirred for 30 minutes. The organiclayer was dried (MgSO₄), filtered and concentrated to an oily residue.100 mL diethyl ether was added and stirred for 4 hours. The product3-[3-amino-4-(2-diethylamino-ethylamino)-phenyl]-acrylic acid methylester was obtained in 54.9% yield (207.6 mg). LCMS m/z: 292 ([M+H]⁺).

Step 4

To a pre-stirred solution of3-[3-amino-4-(2-diethylamino-ethylamino)-phenyl]-acrylic acid methylester (61-2, 1.93 g, 6.65 mmol) and dichloromethane (13.3 mL) was addeda cocktail solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (2.55 g, 13.31 mmol), 1-hydroxybenzotriazole hydrate (2.04g, 13.31 mmol), N,N-diisopropylethylamine (2.20 mL, 13.31 mmol) anddichloromethane (26.6 mL). After stirring for 0.5 h, Fmoc-Gly-OH (61-3,2.97 g, 9.98 mmol) was added. When the starting material has fullyreacted, ethyl acetate (100 mL) was added to dilute the mixture. Theorganic contents were washed with saturated sodium hydrogencarbonate(2×25 mL) and brine (2×25 mL), before drying in sodium sulphate. Themixture was then filtered and concentrated in vacuo. The product3-[3-amino-4-(2-diethylamino-ethylamino)-phenyl]-acrylic acid methylester was obtained in 67.3% yield (2.54 g). LCMS m/z: 571 ([M+H]⁺).

Step 5

Glacial acetic acid (8.9 mL) was added into3-[3-amino-4-(2-diethylamino-ethylamino)-phenyl]-acrylic acid methylester (61-4, 2.54 g, 4.46 mmol) and the reaction mixture was stirred at70° C. for 14 h. When the reaction has completed, the mixture wasconcentrated in vacuo. Saturated sodium hydrogencarbonate (20 mL) wasadded and dichloromethane (3×20 mL) was used to extract the aqueouslayer. The combined organic contents were dried in sodium sulphatebefore being filtered and concentrated in vacuo. The product3-{1-(2-dethylamino-ethyl)-2-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl]-1H-benzoimidazol-5-yl}-acrylicacid methyl ester (61-5) was obtained in 66.1% (1.62 g). LCMS m/z: 553([M+H]⁺).

Step 6

To a pre-stirred solution of3-{1-(2-dethylamino-ethyl)-2-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl]-1H-benzoimidazol-5-yl}-acrylicacid methyl ester (61-5, 1.62 g, 2.94 mmol) and dichloromethane (8.90mL) was added piperidine (1.45 mL, 14.69 mmol). When the reaction hascompleted, the mixture was concentrated in vacuo. The desired productwas separated by reverse phase preparative HPLC. After lyopholyzation,0.52 g (53.6%) of3-[2-aminomethyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-acrylicacid methyl ester was obtained as powder. LCMS m/z: 331 ([M+H]⁺).

Step 7

To a pre-stirred solution of3-[2-aminomethyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-acrylicacid methyl ester (61-6, 0.10 g, 0.23 mmol), N,N-diisopropylethylamine(97 μL, 0.58 mmol) and dichloromethane (1.17 mL) was added2,2-dimethyl-propionyl chloride (34.6 μL, 0.28 mmol) and the resultingreaction mixture was stirred at room temperature for 1 h. When thereaction has completed, ethyl acetate (20 mL) was added to dilute themixture. The organic contents were washed with saturated sodiumhydrogencarbonate (2×20 mL) and brine (2×20 mL), before drying inNa₂SO₄. The mixture was filtered and concentrated in vacuo. The product3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5-yl}-acrylicacid methyl ester (61-7) was obtained in 76.6% (74.1 mg). LCMS m/z: 415([M+H]⁺).

Step 8

To a stirred solution of3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5-yl}-acrylicacid methyl ester (61-7, 73.8 mg, 0.18 mmol) and hydroxylaminehydrochloride (124 mg, 1.78 mmol) in MeOH (0.3 mL) was added sodiummethoxide (30% in methanol) (0.8 mL, 3.6 mmol) at −78° C. The reactionmixture was then allowed to warm up slowly to room temperature. Thereaction was monitored by LC/MS and was completed in around 15 min. 1NHCl was then added slowly into the reaction mixture at 0° C. The desiredproduct was separated by reverse phase preparative HPLC. Afterlyopholyzation, 22.2 mg (24.3%) of3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamidewas obtained as powder. HPLC purity: 99.5%, t_(R)=0.94 min. LCMS m/z:416 ([M+H]⁺). ¹H NMR (CD₃OD) δ 7.89 (s, 1H), 7.84 (d, J=8.5 Hz, 1H),7.73 (d, J=8.4 Hz, 1H), 7.55 (d, J=15.8 Hz, 1H), 6.53 (d, J=15.8 Hz,1H), 4.98 (t, J=7.3 Hz, 2H), 4.73 (s, 2H), 3.75 (t, J=7.5 Hz, 2H), 3.42(q, J=7.2 Hz, 4H), 1.37 (t, J=7.3 Hz, 6H), 1.22 (s, 9H); ¹³C NMR (CD₃OD)δ 182.5, 168.9, 162.2, 161.9, 154.8, 140.8, 137.9, 135.0, 133.9, 126.0,119.3, 117.1, 112.9, 50.9, 40.5, 39.7, 36.7, 27.6, 9.1.

EXAMPLE 58 Preparation ofN-{2-[1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2-yl]-ethyl}-3,3-dimethyl-butyramide(59)

The titled compound (59) was prepared according to the proceduresdescribed in Example 57, by using appropriate starting materials. HPLCpurity at 254 nm: 94.0%; t_(R)=0.99 min. LC-MS m/z: 444 ([M+H]⁺).

EXAMPLE 59 Preparation ofN-[1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2-ylmethyl]-butyramide(62)

The titled compound (62) was prepared according to the proceduresdescribed in Example 57, by using appropriate starting materials. HPLCpurity at 254 nm: 85.1%; t_(R)=0.58 min; LCMS m/z: 402 ([M+H]⁺). ¹H NMR(CD₃OD) δ 7.88-7.56 (m, 2H), 7.73 (s, 1H), 7.60 (d, J=15.8 Hz, 1H), 6.51(d, J=15.8 Hz, 1H), 4.99-4.79 (m, masked peaks), 4.81 (s, 2H), 3.74 (t,J=7.8 Hz, 2H), 3.46-3.41 (m, 4H), 2.31 (t, J=7.4 Hz, 2H), 1.39 (t, J=7.2Hz, 6H), 0.95 (t, J=7.4 Hz, 3H); ¹³C NMR (CD₃OD) δ117.1, 165.9, 154.6,140.9, 129.6, 128.4, 127.3, 125.9, 118.6, 112.8, 111.5, 50.7, 40.4,38.4, 36.4, 19.9, 14.0, 9.0.

EXAMPLE 60 Preparation of3-[2-(3,3-Dimethyl-butyl)-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(63)

The titled compound (63) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLC:99.0%; t_(R)=0.93 min; LCMS m/z: 359 ([M+H]⁺). ¹H NMR (CD₃OD) δ 7.5 (d,J=8.4 Hz, 1H), 7.75-7.74 (m, 2H), 7.16 (d, J=15.7 Hz, 1H), 6.31 (d,J=15.7 Hz, 1H), 4.89 (brs, 2H), 3.72 (brs, 2H), 3.29-3.18 (m, 4H),1.90-1.86 (m, 2H), 1.35 (t, J=7.1 Hz, 3H), 1.09 (s, 9H); ¹³C NMR (CD₃OD)δ 165.7, 158.4, 140.4, 134.9, 134.5, 134.2, 126.2, 122.5, 119.2, 115.6,113.4, 55.3, 44.0, 40.8, 40.7, 31.3, 29.3, 22.9.

EXAMPLE 61 Preparation of3-[1-(2-Dimethylamino-ethyl)-2-(3,3-dimethyl-butyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(64)

The titled compound (64) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLC:99.0%; t_(R)=0.83 min; LCMS m/z: 359 ([M+H]⁺). ¹H NMR (CD₃OD) δ7.94 (d,J=7.8 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.42 (d, J=15.7 Hz,1H), 6.64 (d, J=15.7 Hz, 1H), 4.93 (brs, 2H), 3.76 (brs, 2H), 3.22 (t,J=7.7 Hz, 2H), 3.09 (s, 6H), 1.91-1.87 (m, 2H), 1.08 (s, 9H); ¹³C NMR(CD₃OD) δ 165.4, 158.4, 140.2, 134.5, 134.2, 133.2, 126.5, 118.8, 115.3,113.9, 46.4, 45.1, 42.9, 40.6, 31.3, 29.2, 22.9, 11.4.

EXAMPLE 62 Preparation of3-[1-(2-Dimethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(65)

The titled compound (65) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 98.5%; t_(R)=0.78 min. LCMS m/z: 345 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.89 (3H, m), 1.38 (4H, m), 1.83 (2H, m), 2.93 (6H, s), 3.04(2H, m), 3.50 (2H, t), 4.70 (2H, m), 6.55 (1H, d), 7.57 (1H, d), 7.61(1H, m), 7.81 (2H, m), 10.42 (1H, bs).

EXAMPLE 63 Preparation of3-[1-(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(64)

The titled compound (64) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 91.1%; t_(R)=0.68 min. LCMS m/z: 357 ([M+H]⁺).

EXAMPLE 64 Preparation of3-[1-(2-Ethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(68)

The titled compound (68) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 98.4%; t_(R)=0.87 min. LCMS m/z: 345 ([M+H]⁺).

EXAMPLE 65 Preparation ofN-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-acrylamide(71)

The titled compound (71) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 97.4%; t_(R)=0.95 min. LCMS m/z: 359 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.89 (3H, m), 1.22 (6H, d), 1.38 (4H, m), 1.82 (2H, m), 2.99(3H, m), 4.56 (2H, m), 6.51 (1H, d), 7.59 (2H, d), 7.64 (1H, m), 7.88(1H, m), 8.74 (2H, bs).

EXAMPLE 66 Preparation of3-[2-Hexyl-1-(2-methylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(74)

The titled compound (74) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 96.0%, t_(R)=1.12 min. LCMS m/z: 345 ([M+H]⁺). ¹H NMR(CD₃OD) δ 7.76 (2H, s), 7.70 (1H, d, J=8.6 Hz). 7.50 (1H, d, J=15.7 Hz),6.43 (1H, d, J=15.7 Hz), 4.81 (2H, d, J=5.7 Hz), 3.49 (2H, bs), 3.15(2H, dt, J=4.8 Hz), 2.71 (3H, s), 1.85 (2H, qn, J=5.1 Hz), 1.46 (2H, m),1.33 (4H, m), 0.85 (3H, t, J=7.1 Hz); ¹³C NMR (CD₃OD) δ 163.7, 157.8,138.5, 132.7, 124.2, 117.6, 113.7, 111.2, 40.2, 32.2, 30.5, 28.0, 25.6,25.1, 21.6, 12.3.

EXAMPLE 67 Preparation ofN-Hydroxy-3-[1-(2-methylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-acrylamide(75)

The titled compound (75) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity at 254 nm: 97.8%; t_(R)=0.80 min. LCMS m/z: 331 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.89 (3H, m), 1.38 (4H, m), 1.84 (2H, m), 2.51 (3H, s), 3.14(2H, m), 3.38 (2H, t), 4.70 (2H, m), 6.57 (1H, d), 7.62 (1H, d), 7.73(1H, m), 7.96 (2H, m), 9.13 (2H, s).

EXAMPLE 68 Preparation of3-(2-Butyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(69)

Step 1.

To a solution of methyl trans-4-Chloro-3-nitrocinnamate (Ia, 4.8 g, 20mmol) in triethyl amine (5.5 mL, 40 mmol) was added3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (11.2 g, 60mmol), the resulting mixture was then heated to 100° C. for 8 hours,then another portion of methyl trans-4-Chloro-3-nitrocinnamate (4.8 g,20 mmol) and triethyl amine (5.5 mL, 40 mmol) was added, the resultingmixture was allowed to stir overnight at 100° C., then reaction wasquenched by adding 200 mL of DCM and 80 mL of 1M HCl solution. Afterseparation of DCM layer, the aqueous solution was extracted with DCM onemore time, and combined with previous DCM solution, which was thenwashed with brine, dried over sodium sulfate, then filtered throughsilica gel short column, and rinsed with ethyl acetate and hexanesmixture (2:1) until the orange color band was completely rinsed down.After removal of solvent under reduced pressure, the residue 69-2 wasobtained (around 80% of yield in most of cases) as orange solid, whichis pure enough (95% purity from HPLC) for next step. LC-MS m/z: 292([M-Boc+H]⁺).

Step 2.

To a solution of compound 69-2 (7.84 g, 20.0 mmol) in 100 mL of MeOH andAcOH mixture (1:9) was added corresponding aldehyde (3.0 mL, 30.0 mmol)and tin chloride (22.6 g, 100 mmol), the resulting mixture was stirredat 42° C. for 24 hrs. Then the mixture was diluted using ethyl acetate(300 mL) at room temperature, and was then quenched with sat. sodiumcarbonate (30 mL). The resulting mixture was stirred for additional 1hour, then organic layer was decanted to another conic flask. Solid leftin reaction flask was suspension with another portion of ethyl acetate(300 mL), which was then decanted and combined with previous portion ofethyl acetate and was then filtered through silica gel short column andrinsed with ethyl acetate, after removal of filtrate under reducedpressure, the residue was pure enough for next step and also could bepurified on column (hexanes:EtOAc=1:2) to give a pale-yellow solid 69-3(3.8 g, 44%). LC-MS m/z: 456 ([M+H]⁺).

Step 3.

To a flask charged with compound 69-3 (456 mg, 1 mmol) was added 1.25 MHCl in MeOH (4 mL), the resulting mixture was then heated to reflux for2 hours, which was then evaporated to dryness under reduced pressure togive compound 4 as HCl salt, which is pure enough for next step withoutany purification. LC-MS m/z: 356 ([M+H]⁺).

Step 4.

To a solution of above crude 69-4 (around 0.16 mmol) product in MeOH(0.5 mL) was added a pre-prepared NH₂OH stock solution (2.0 M, 2 mL).The resulting mixture was stirred at room temperature for 2 hrs. Afterquenching with TFA (0.4 mL), the resulting mixture was subjected to HPLCpurification to afford 25 mg of3-(2-Butyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide.HPLC purity: 98%; LC-MS m/z: 329 ([M+H]⁺). ¹H NMR (CD₃OD) δ 0.95 (3H, t,J=7.2 Hz), 1.46 (2H, m), 1.77 (2H, m), 2.52-2.82 (2H, m), 3.10-3.17 (2H,m), 3.48 (1H, m), 3.80 (2H, m), 5.55 (1H, m), 6.48 (1H, d, J=16.0 Hz),7.58 (1H, d, J=16.0 Hz), 7.67 (1H, d, J=8.0 Hz), 7.78-7.92 (2H, m).

EXAMPLE 69 Preparation of3-(2-Butyl-1-piperidin-4-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(70)

The titled compound (70) was prepared according to the proceduresdescribed in Example 78, by using appropriate starting materials. HPLCpurity: 98%; LCMS m/z: 343 ([M+H]⁺). ¹H NMR (CD₃OD) δ 0.96 (3H, t, J=7.2Hz), 1.46 (2H, m), 1.79 (2H, m), 2.21 (2H, m), 2.82 (2H, m), 3.10-3.17(2H, m), 3.26 (1H, m), 3.60 (2H, m), 4.96 (1H, m), 6.49 (1H, d, J=15.8Hz), 7.60 (1H, d, J=15.8 Hz), 7.66 (1H, d, J=8.0 Hz), 7.82 (1H, s) (1H,d, J=8.0 Hz).

EXAMPLE 70 Preparation of3-(2-Hexyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(80)

The titled compound (80) was prepared according to the proceduresdescribed in Example 68, by using appropriate starting materials. HPLCpurity: 98%; LCMS m/z: 357 ([M+H]⁺). ¹H NMR (CD₃OD) δ 0.84 (3H, t, J=7.2Hz), 1.22-1.38 (4H, m), 1.44 (2H, m), 1.81 (2H, m), 2.52-2.82 (2H, m),3.10-3.17 (2H, m), 3.48 (1H, m), 3.80 (2H, m), 5.56 (1H, m), 6.48 (1H,d, J=15.8 Hz), 7.56 (1H, d, J=15.8 Hz), 7.65 (1H, d, J=9.2 Hz), 7.84(1H, s), 7.90 (1H, d, J=9.2 Hz).

EXAMPLE 71 Preparation of3-[2-Butyl-1-(1-methyl-pyrrolidin-3-yl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(81)

The titled compound (81) was prepared according to the proceduresdescribed in Example 68, by using 69-4 via reductive amination tointroduce a methyl group. HPLC purity: 98%; LCMS m/z: 343 ([M+H]⁺). ¹HNMR (CD₃OD) δ 0.99 (3H, t, J=7.2 Hz), 1.52 (2H, m), 1.83 (2H, m),2.65-2.92 (2H, m), 3.09 (3H, s), 3.15-3.25 (2H, m), 3.58 (1H, br.), 3.90(2H, m), 5.73 (1H, m), 6.51 (1H, d, J=16.0 Hz), 7.58 (1H, d, J=16.0 Hz),7.69 (1H, d, J=8.0 Hz), 7.88 (1H, s), 8.00 (1H, d, J=9.2 Hz).

EXAMPLE 72 Preparation of3-(2-Hexyl-1-piperidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(82)

The titled compound (82) was prepared according to the proceduresdescribed in Example 68, by using appropriate starting materials. HPLCpurity: 97%; LCMS m/z: 343 ([M+H]⁺). ¹H NMR (CD₃OD) δ 0.99 (3H, t, J=7.2Hz), 1.52 (2H, m), 1.84 (2H, m), 2.04 (1H, m), 2.20 (2H, m), 2.61 (1H,m), 3.12-3.22 (2H, m), 3.49 (1H, m), 3.67 (1H, m), 3.78 (1H, t, J=12.0Hz), 4.98 (1H, m), 6.53 (1H, d, J=15.8 Hz), 7.63 (1H, d, J=15.8 Hz),7.70 (1H, d, J=9.2 Hz), 7.86 (1H, s), 8.06 (1H, d, J=8.8 Hz).

EXAMPLE 73 Preparation of3-(2-Butyl-1-piperidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(83)

The titled compound (83) was prepared according to the proceduresdescribed in Example 68, by using appropriate starting materials. HPLCpurity: 97%; LCMS m/z: 371 ([M+H]⁺). ¹H NMR (CD₃OD) δ 0.88 (3H, t, J=7.2Hz), 1.22-1.42 (4H, m), 1.47 (2H, m), 1.84 (2H, m), 2.04 (1H, m), 2.20(2H, m), 2.62 (1H, m), 3.12-3.22 (2H, m), 3.48 (1H, m), 3.68 (1H, m),3.78 (1H, t, J=12.0 Hz), 5.01 (1H, m), 6.53 (1H, d, J=15.8 Hz), 7.62(1H, d, J=15.8 Hz), 7.70 (1H, d, J=9.2 Hz), 7.86 (1H, s), 8.06 (1H, d,J=8.8 Hz).

EXAMPLE 74 Preparation of(E)-N-hydroxy-3-(1-(1-methylpiperidin-3-yl)-2-pentyl-1H-benzo[d]imidazol-5-yl)acrylamide(86)

The titled compound (86) was prepared according to the proceduresdescribed in Example 71, by using appropriate starting materials. HPLCpurity: 99.3%, t_(R)=1.06 min; LCMS m/z: 371 ([M+H]⁺). ¹H NMR (CD₃OD) δ8.18 (d, J=7.9 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.61 (d,J=15.7 Hz, 1H), 6.58 (d, J=15.7 Hz, 1H), 5.21 (brs, 1H), 3.69 (brs, 2H),3.69-3.66 (m, 1H), 3.37-3.27 (masked peaks), 3.03 (s, 3H), 2.66 (brs,1H), 2.29-2.22 (m, 3H), 1.94-1.90 (m, 2H), 1.54-0.94 (m, 4H), 0.96 (t,J=7.1 Hz, 3H); ¹³C NMR (CD₃OD) δ165.6, 157.6, 139.9, 134.6, 134.1,132.5, 126.3, 120.4, 115.5, 115.2, 54.9, 54.4, 53.3, 44.1, 32.4, 27.5,27.3, 26.8, 23.2, 23.1, 14.2.

EXAMPLE 75 Preparation of(E)-3-(2-hexyl-1-(1-(2-hydroxyethyl)piperidin-3-yl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide(90)

The titled compound (90) was prepared according to the proceduresdescribed in Example 68, by using appropriate starting materials andalkylation of the piperidine with 2-bromoethanol. LCMS m/z: 415([M+H]⁺).

EXAMPLE 76 Preparation ofN-Hydroxy-3-[1-(1-pentyl-piperidin-3-yl)-1H-benzoimidazol-5-yl]-acrylamide(94)

The titled compound (94) was prepared according to the proceduresdescribed in Example 68, by using appropriate starting materials (formicacid for benzimidazole ring formation and reductive amination of thepiperidine with pentanal). HPLC purity: 95%; LC-MS m/z: 357 ([M+H]⁺). ¹HNMR (CD₃OD) δ 9.04 (s, 1H), 7.94 (brs, 2H), 7.78 (d, 1H, J=8.2 Hz), 7.70(d, 1H, J=15.7 Hz), 6.57 (d, 1H, J=15.9 Hz), 5.14-5.10 (m, 1H), 3.85(dd, 2H, J=88.0, 9.0 Hz), 3.48-3.13 (m, 4H), 2.43-2.12 (m, 4H),1.94-1.80 (m, 2H), 1.39-1.29 (m, 4H), 0.94 (t, 3H, J=6.8 Hz).

EXAMPLE 77 Preparation ofN-Hydroxy-3-[1-(1-phenethyl-piperidin-3-yl)-1H-benzoimidazol-5-yl]-acrylamide(96)

The titled compound (96) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 98.6%; LC-MS m/z: 391 ([M+H]⁺). ¹H NMR (CD₃OD) δ 8.93 (s, 1H),7.95 (s, 1H), 7.91 (d, 1H, J=8.5 Hz), 7.76 (d, 1H, J=8.5 Hz), 7.70 (d,1H, J=15.8 Hz), 7.35-7.24 (m, 6H), 6.56 (d, 1H, J=15.7 Hz), 5.10 (t, 1H,J=11.4 Hz), 3.91 (dd, 2H), 3.55-3.45 (m, 2H), 3.15-3.11 (m, 2H),2.46-2.13 (m, 6H).

EXAMPLE 78 Preparation ofN-Hydroxy-3-{1-[1-(3-phenyl-propyl)-piperidin-3-yl]-1H-benzoimidazol-5-yl}-acrylamide(97)

The titled compound (97) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 94.5%; LC-MS: 405 ([M+H]⁺) ¹H NMR (CD₃OD) δ 8.68 (s, 1H), 7.94(s, 1H), 7.80 (d, 1H, J=8.4 Hz), 7.71 (d, 1H, J=15.7 Hz), 7.69 (d, 1H,J=8.2 Hz), 7.31-7.17 (m, 6H), 6.54 (d, 1H, J=15.6 Hz), 3.71 (dd, 2H,J=66 Hz, 10.9 Hz), 3.48-3.40 (m, 1H), 3.13-3.05 (m, 2H), 2.73 (t, 2H,J=7.4 Hz), 2.38-2.04 (m, 8H).

EXAMPLE 79 Preparation of3-{1-[1-(3,3-Dimethyl-butyl)-pyrrolidin-3-yl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(99)

The titled compound (99) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 91.9%; t_(R)=1.10 min. LC-MS m/z: 357 ([MH]⁺). ¹H NMR (DMSO-d₆)δ 0.91 (9H, s), 1.52 (4H, m), 3.09 (1H, m), 3.29 (6H, m), 6.52 (1H, d),7.43 (2H, m), 7.62 (1H, m), 7.80 (1H, m), 8.82 (1H, s), 10.25 (1H, bs).

EXAMPLE 80 Preparation of3-{1-[2-(Ethyl-methyl-amino)-ethyl]-2-pentyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(79)

The titled compound (79) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity: 99%; t_(R)=0.68 min. LC-MS m/z: 359 ([M+H]⁺). ¹H NMR (DMSO-d₆) δ0.89 (3H, m), 1.23 (3H, m), 1.38 (4H, m), 1.84 (2H, m), 2.92 (3H, s),3.10 (2H, m), 3.28 (2H, m), 3.52 (2H, m), 4.77 (2H, m), 6.58 (1H, d),7.61 (1H, d), 7.71 (1H, m), 7.92 (2H, m), 10.48 (1H, bs).

EXAMPLE 81 Preparation of3-{2-Butyl-1-[2-(ethyl-methyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(85)

The titled compound (85) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity: 95.8%; t_(R)=1.04 min. LC-MS m/z: 345 ([M+H]⁺). ¹H NMR (DMSO-d₆)δ 0.95 (3H, m), 1.25 (3H, m), 1.46 (2H, m), 1.81 (2H, m), 2.92 (3H, s),3.13 (2H, m), 3.27 (2H, m), 3.54 (2H, m), 4.80 (2H, m), 6.60 (1H, d),7.62 (1H, d), 7.75 (1H, m), 7.92 (2H, m), 10.59 (1H, bs).

EXAMPLE 82 Preparation of3-(2-Butyl-1-{2-[ethyl-(3-hydroxy-propyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(91)

The titled compound (91) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity: 93.5%; t_(R)=0.50 min. LC-MS (m/z): 389 ([MH]⁺). ¹H NMR(DMSO-d₆) δ 0.94 (3H, m), 1.25 (3H, m), 1.46 (2H, m), 1.83 (4H, m), 3.04(2H, m), 3.31 (4H, m), 3.50 (4H, m), 4.72 (2H, m), 6.54 (1H, d), 7.61(1H, m), 7.69 (1H, m), 7.80 (1H, m), 7.90 (1H, m), 10.20 (1H, bs).

EXAMPLE 83 Preparation of3-(1-{2-[Ethyl-(3-hydroxy-propyl)-amino]-ethyl}-2-pentyl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(92)

The titled compound (92) was prepared according to the proceduresdescribed in Example 1, by using appropriate starting materials. HPLCpurity: 93.5%; t_(R)=0.50 min. LC-MS (m/z): 389 ([M+H]⁺) ¹H NMR(DMSO-d₆) δ 0.94 (3H, m), 1.25 (3H, m), 1.46 (2H, m), 1.83 (4H, m), 3.04(2H, m), 3.31 (4H, m), 3.50 (4H, m), 4.72 (2H, m), 6.54 (1H, d), 7.61(1H, m), 7.69 (1H, m), 7.80 (1H, m), 7.90 (1H, m), 10.20 (1H, bs).

EXAMPLE 84 Preparation of3-{1-[2-(Butyl-ethyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(95)

The titled compound (95) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 99.9%; LC-MS m/z: 331 ([M+H]⁺). ¹H NMR (CD₃OD) δ 9.29 (s, 1H),7.99-7.95 (m, 2H), 7.82 (d, 1H, J=8.5 Hz), 7.56 (d, 1H, J=15.6 Hz), 6.53(d, 1H, J=15.5 Hz), 5.0-4.95 (m, 2H), 3.86-3.78 (m, 2H), 3.42 (dd, 2H,J=13.3, 7.1 Hz), 3.28-3.26 (m, 2H), 1.74-1.71 (m, 2H), 1.43 (qt, 2H,J=7.4, 3.8 Hz), 1.38 (t, 3H, J=7.2 Hz), 1.00 (t, 3H, J=7.3 Hz).

EXAMPLE 85 Preparation of3-[2-(4-Cyano-butyl)-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(101)

The titled compound (101) was prepared according to the proceduresdescribed in Example 57, by using appropriate starting materials. HPLCpurity at 254 nm: 99.9%. LC-MS (ESI) m/z: 384 ([M+H]⁺). ¹H NMR (CD₃OD) δ7.78 (1H, s) 7.76 (1H, d, J=8.5 Hz), 7.63 (1H, d, J=16.9 Hz), 7.58 (1H,d. J=5.1 Hz), 6.44 (1H, d, J=15.3 Hz), 4.70 (2H, in water peak), 3.50(2H, t, J=7.6 Hz), 3.32 (4H, qt, J=7.3 Hz), 3.07 (2H, t, J=8.0 Hz), 2.50(2H, t, J=7.0 Hz), 1.99 (2H, q, J=7.5 Hz), 1.78 (2H, q, J=7.3 Hz), 1.29(6H, t, J=7.3 Hz).

EXAMPLE 86 Preparation of3-{1-[2-(Butyl-isopropyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(108)

The titled compound (108) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 98.8%; t_(R)=1.33 min. LC-MS m/z: 345 ([M+H]⁺). ¹H NMR (DMSO-d₆)δ 0.90 (3H, m), 1.25 (6H, d), 1.35 (2H, m), 1.64 (2H, m), 3.09 (2H, m),3.51 (1H, m), 3.73 (2H, m), 4.74 (2H, m), 6.52 (1H, d), 7.53 (2H, m),7.64 (1H, m), 7.80 (1H, m), 8.62 (1H, m), 9.40 (1H, bs), 10.72 (1H, bs).

EXAMPLE 87 Preparation ofN-Hydroxy-3-{1-[2-(isopropyl-pentyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-acrylamide(109)

The titled compound (109) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. LC-MSm/z: 359 ([M+H]⁺). ¹H NMR (DMSO-d₆) δ 0.88 (3H, t), 1.25 (10H, m), 1.64(2H, m), 3.12 (2H, m), 3.51 (1H, b), 3.60 (1H, b), 3.73 (1H, b), 4.74(2H, t), 6.51 (1H, d), 7.59 (1H, s), 7.63 (1H, d), 7.80 (1H, d), 7.93(1H, s), 8.65 (1H, s), 9.46 (1H, b).

EXAMPLE 88 Preparation of3-[2-(5-Cyano-pentyl)-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(110)

The titled compound (110) was prepared according to the proceduresdescribed in Example 57, by using appropriate starting materials. HPLCpurity at 254 nm: 95.4%. LC-MS (ESI) m/z: 347 ([M+H]⁺). ¹H NMR (CD₃OD) δ7.96 (1H, d, J=8.5 Hz), 7.90 (1H, s) 7.81 (1H, d, J=8.5 Hz), 7.59 (1H,d. J=15.6 Hz), 6.55 (1H, d, J=15.5 Hz), 4.96 (2H, t, J=7.3 Hz), 3.69(2H, t, J=7.1 Hz), 3.44 (4H, qt, J=7.2 Hz), 3.31 (2H, embedded in MeODpeak), 2.51 (2H, t, J=6.9 Hz), 2.05-1.98 (2H, m), 1.78 (2H, m, J=7.4Hz), 1.70 (2H, m, J=6.4 Hz), 1.41 (3H, t, J=7.2 Hz).

EXAMPLE 89 Preparation of3-(1-{2-[(3,3-Dimethyl-butyl)-ethyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(111)

The titled compound (111) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. TFAsalt. HPLC purity: 97.7%; LC-MS m/z: 359 ([M+H]⁺). ¹H NMR (CD₃OD) δ 9.10(s, 1H), 7.89 (d, 1H, J=8.9 Hz), 7.88 (s, 1H), 7.74 (d, 1H, J=8.6 Hz),7.51 (d, 1H, J=15.7 Hz), 6.46 (d, 1H, J=15.7 Hz), 4.98-4.93 (m, 2H),3.77-3.75 (m, 2H), 3.38 (dd, 2H, J=13.3, 7.2 Hz), 3.22-3.18 (m, 2H),1.60-1.59 (m, 2H), 1.33 (t, 3H, J=7.1 Hz), 0.91 (s, 9H).

HCl salt. ¹H NMR (DMSO-d₆) δ 9.90 (bs, 1H), 8.65 (s, 1H), 7.93 (s, 1H),7.82 (d, 1H, J=8.5 Hz), 7.64 (d, 1H, J=8.1 Hz), 7.61 (d, 1H, J=15.6 Hz),7.52 (d, 1H, J=15.8 Hz), 4.76-4.72 (t, 2H, J=7.0), 3.65-3.60 (m, 2H),3.32-3.24 (m, 2H), 3.17-3.08 (m, 2H), 1.52-1.47 (m, 2H), 1.22 (t, 3H,J=7.2 Hz), 0.87 (s, 9 Hz).

EXAMPLE 90 Preparation of3-{1-[2-(Ethyl-propyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(112)

The titled compound (112) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 98.1%; LC-MS m/z: 315 ([M+H]⁺). ¹H NMR (CD₃OD) δ 9.43 (s, 1H),7.99 (d, 1H, J=8.5 Hz), 7.93 (s, 1H), 7.82 (d, 1H, J=8.5 Hz), 7.53 (d,1H, J=15.7 Hz), 6.50 (d, 1H, J=15.5 Hz), 5.00-4.96 (m, 2H), 3.78 (t, 2H,J=6.1 Hz), 3.37 (dd, 2H, J=14.2, 7.2 Hz), 3.22-3.19 (m, 2H), 1.75 (qt,2H, J=7.5 Hz), 1.33 (t, 3H, J=7.2 Hz), 0.99 (t, 3H, J=7.3 Hz).

EXAMPLE 91 Preparation ofN-Hydroxy-3-(1-{2-[isopropyl-(2-methyl-pentyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-acrylamide(113)

The titled compound (113) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. LC-MSm/z: 373-[(M+H)⁺]]. ¹H NMR (DMSO-d₆) δ 0.86-0.97 (7H, m), 1.14-1.28(12H, m), 4.70 (2H, b), 6.49 (1H, d), 7.58-7.62 (2H, m), 7.73 (1H, d),7.91 (1H, s), 8.48 (1H, s).

EXAMPLE 92 Preparation of3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-methyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(116)

The titled compound (116) was prepared according to the proceduresdescribed in Example 57, by using appropriate starting materials. HPLCpurity at 254 nm: 98.2%, t_(R)=1.27 min. LC-MS (ESI) m/z: 373 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.85 (1H, s), 7.78 (1H, d, J=8.4 Hz), 7.70 (1H, d,J=8.7 Hz), 7.15 (1H, d. J=15.9 Hz), 6.53 (1H, d, J=15.9 Hz), 4.81 (2H),3.63 (2H, t, J=7.7 Hz), 3.41 (2H, qt, J=7.2 Hz), 3.29 (2H), 2.82 (3H,s), 1.74 (2H, m), 1.37 (11H, m), 0.93 (3H, t, J=6.9 Hz).

EXAMPLE 93 Preparation of3-{1-[2-(Butyl-ethyl-amino)-ethyl]-2-trifluoromethyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(117)

The titled compound (117) was prepared according to the proceduresdescribed in Example 57, by using appropriate starting materials. HPLCpurity at 254 nm: 97.3%, t_(R)=1.50 min. LC-MS (ESI) m/z: 399 ([M+H]⁺).¹H NMR (CD₃OD) δ 7.95 (1H, s), 7.70 (2H, s), 7.62 (1H, d, J=15.9 Hz),6.46 (1H, d, J=15.8 Hz), 5.24 (2H), 3.50 (2H, t, J=8.8 Hz), 3.31 (2H,qt, J=7.2 Hz), 3.17 (2H), 1.63 (2H, m), 1.35 (2H, qt, J=7.5 Hz), 1.29(3H, t, J=7.2 Hz), 0.92 (3H, t, J=7.4 Hz).

EXAMPLE 94 Preparation of3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-trifluoromethyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(118)

The titled compound (118) was prepared according to the proceduresdescribed in Example 57, by using appropriate starting materials. HPLCpurity at 254 nm: 94.6%, t_(R)=2.07 min. LC-MS (ESI) m/z: 427 ([M+H]⁺).¹H NMR (CD₃OD) δ 8.04 (1H, s), 7.80 (2H, s), 7.72 (1H, d, J=15.8 Hz),6.56 (1H, d, J=15.6 Hz), 4.85 (2H), 3.61 (2H, t, J=8.5 Hz), 3.42 (2H,qt, J=7.2 Hz), 3.26 (2H), 1.75 (2H, m), 1.39 (9H, m, J=7.5 Hz), 0.93(3H, t, J=7.0 Hz).

EXAMPLE 95 Preparation of3-[1-(2-Dipropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(120)

The titled compound (120) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 100%. LC-MS m/z: 331 ([M+H]⁺). ¹H NMR (DMSO-d₆) δ 0.86 (6H, d),1.64 (4H, m), 3.09 (4H, m), 3.60 (2H, m), 4.76 (2H, m), 6.53 (1H, d),7.55 (2H, m), 7.65 (1H, m), 7.88 (1H, m), 8.75 (1H, m), 9.93 (1H, bs).

EXAMPLE 96 Preparation ofN-Hydroxy-3-(1-{2-[isopropyl-(3-methyl-butyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-acrylamide(121)

The titled compound (121) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 98.7%; t_(R)=1.02 min. LC-MS (m/z): 358 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.88 (6H, d), 1.28 (6H, m), 1.59 (3H, m), 3.10 (3H, m), 3.68(2H, m), 4.71 (2H, m), 6.50 (1H, d), 7.50 (2H, m), 7.59 (1H, m), 7.63(1H, m), 8.52 (1H, m), 9.50 (1H, bs), 10.70 (1H, bs).

EXAMPLE 97 Preparation of3-(1-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(122)

The titled compound (122) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity at 254 nm: 97.8%; t_(R)=0.93 min. LC-MS m/z: 345 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.84 (9H, s), 1.52 (2H, m), 2.90 (3H, s), 3.17 (2H, m), 3.68(2H, m), 4.80 (2H, m), 6.58 (1H, d), 7.59 (2H, m), 7.86 (1H, m), 7.90(1H, m), 8.82 (1H, m), 10.10 (1H, bs).

EXAMPLE 98 Preparation of3-(1-{2-[(2-Ethyl-butyl)-methyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(123)

The titled compound (123) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity at 254 nm: 97.7%; t_(R)=0.87 min. LC-MS m/z: 345 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 0.81 (6H, m), 1.29 (4H, m), 1.69 (1H, m), 2.89 (3H, s), 3.08(2H, m), 3.59 (2H, m), 4.77 (2H, m), 6.53 (1H, d), 7.52 (2H, m), 7.86(1H, m), 7.94 (1H, m), 8.80 (1H, m), 9.54 (1H, bs).

EXAMPLE 99 Preparation of3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(126)

The titled compound (126) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 100%; t_(R)=1.01 min. LC-MS m/z: 331 ([M+H]⁺). ¹H NMR (DMSO-d₆)δ 0.88 (9H, s), 1.44 (2H, m), 2.92 (2H, m), 3.50 (2H, m), 4.66 (2H, m),6.54 (1H, d), 7.58 (2H, m), 7.82 (1H, m), 7.90 (1H, m), 8.74 (1H, m).

EXAMPLE 100 Preparation ofN-Hydroxy-3-{1-[2-(methyl-pent-4-enyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-acrylamide(127)

The titled compound (127) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 100%; t_(R)=0.92 min. LC-MS m/z: 329 ([M+H]⁺). ¹H NMR (DMSO-d₆)δ 1.17 (2H, m), 2.06 (2H, m), 2.90 (3H, s), 3.10 (2H, m), 3.65 (2H, m),4.80 (2H, m), 5.03 (2H, m), 5.75 (1H, m), 6.57 (1H, d), 7.60 (1H, d),7.69 (1H, m), 7.90 (1H, m), 7.97 (1H, m), 8.92 (1H, m), 10.29 (1H, bs).

EXAMPLE 101 Preparation of3-(1-{2-[(3,3-Dimethyl-butyl)-propyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(128)

The titled compound (128) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 99.0%; t_(R)≈1.18 min. LC-MS m/z: 373 ([M+H]⁺). ¹H NMR (DMSO-d₆)δ 0.88 (12H, m), 1.51 (2H, m), 1.64 (2H, m), 3.10 (4H, m), 3.63 (2H, m),4.76 (2H, m), 6.54 (1H, d), 7.65 (2H, m), 7.80 (1H, m), 7.94 (1H, m),8.83 (1H, m), 9.93 (1H, bs).

EXAMPLE 102 Preparation of3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-propyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(130)

Step 1: Cyclization

To the starting material (IIIa2, 3.34 g, 12.6 mmol) in 20% AcOH in MeOH(33 mL, 0.2 M) was added butyraldehyde (1.7 mL, 18.9 mmol) followed byzinc powder (4.12 g, 63 mmol). The resulting mixture was heat up to 50°C. and stirred at this temperature for 30 minutes. The completion ofreaction was monitored by HPLC and LCMS. The solvent was then evaporatedto dryness and the crude was dissolved with ethyl acetate, subsequentlysaturated aqueous sodium carbonate was added till pH=9 and the mixturewas centrifuged spin at 9000 rpm for 10 min. The liquid was decanted andsolid was rinsed with ethyl acetate (sonicated). The liquid wasextracted with ethyl acetate and then purified by flash chromatography(silica, 3% MeOH in DCM) to give3-[1-(2-Amino-ethyl)-2-propyl-1H-benzoimidazol-5-yl]-acrylic acid methylester. Yield=25%, LC-MS m/z: 288 ([M+H]⁺).

Step 2: Reductive-Amination

To 3-[1-(2-Amino-ethyl)-2-propyl-1H-benzoimidazol-5-yl]-acrylic acidmethyl ester (1.2 g, 4.2 mmol) in MeOH (40 mL) was added3,3-Dimethyl-butyraldehyde (0.524 mL, 4.2 mmol). The resulting mixturewas stirred at rt for 2 hours prior to the addition of acetic acid (2mL) and sodium cyanoborohydride (0.395 g, 6.3 mmol) and the reaction wasstirred at rt for another 30 minutes. Solvent was removed and theresidual was dissolved in DCM upon which was washed with aqueous sodiumbicarbonate, water and brine. The is combined organic layer, afterworkup, was purified by flash chromatography (silica, 4% MeOH in DCM).LC-MS m/z: 372 ([M+H]⁺).

Step 3: Hydroxamic Acid Formation.

The titled compound (130) was prepared according to the proceduresdescribed in Example 1 (Step 4), by using appropriate startingmaterials.

TFA salt of 130: HPLC purity: 99.9%; LC-MS m/z: 373 ([M+H]⁺). ¹H NMR(CD₃OD) δ 7.89 (d, 1H, J=8.6 Hz), 7.81 (s, 1H), 7.76 (d, 1H, J=8.6 Hz),7.44 (d, 1H, J=15.7 Hz), 6.44 (d, 1H, J=15.7 Hz), 4.81 (t, 2H, J=7.0Hz), 3.65 (t, 2H, J=6.4 Hz), 3.23-3.19 (m, 2H), 3.16-3.12 (m, 2H),2.01-1.94 (m, 2H), 1.65-1.61 (m, 2H), 1.16 (t, 3H, 7.3 Hz), 0.96 (s,9H). Dihydrochloride salt of 130 was prepared according to theprocedures described in Example 50, Step 4 and 5, by using appropriatestarting materials. HPLC purity: 98.1%; LC-MS m/z: 373 ([M+H]⁺). ¹H NMR(DMSO-d₆) δ 10.89 (1H, br s), 9.77 (2H, b, —NH₂ ⁺—), 8.12 (1H, d, J=8.6Hz), 7.97 (1H, s), 7.78 (1H, d, J=8.5 Hz), 7.64 (1H, d, J=15.8 Hz), 6.64(1H, d, J=15.8 Hz), 4.88 (2H, t, J=5.8 Hz), 3.41 (2H, m), 3.26 (2H, t,J=7.6 Hz), 2.91 (2H, m), 1.90 (2H, sextet, J=7.6 Hz), 1.56 (2H, m), 1.05(3H, t, J=7.3 Hz), 0.88 (9H, s); ¹³C NMR (DMSO-d₆) δ 162.4, 155.9, 137.4(CH), 132.8, 132.4, 131.8 (br), 124.6 (CH), 120.2 (CH), 113.2 (CH),113.0 (CH), 44.9, 44.0, 41.1, 38.6, 29.4 (Cq), 28.9, 27.1, 19.9, 13.5.

EXAMPLE 103 Preparation of3-[1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(131)

The titled compound (131) was prepared according to the proceduresdescribed in Example 102, by using appropriate starting materials. HPLCpurity: 92%; LC-MS m/z: 401 ([M+H]⁺). ¹H NMR (CD₃OD) δ 7.89 (s, 1H),7.85 (d, 1H, J=8.5 Hz), 7.77 (d, 1H, J=108.7 Hz), 7.63 (d, 1H, J=15.8Hz), 6.55 (d, 1H, J=15.7 Hz), 4.91-4.81 (m, 2H), 3.58 (t, 2H, J=6.5 Hz),3.13-3.08 (m, 4H), 1.63-1.58 (m, 2H), 1.13 (s, 9H), 0.96 (s, 9H).

EXAMPLE 104 Preparation of3-[1-{2-[Bis-(3,3-dimethyl-butyl)-amino]-ethyl}-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(132)

The titled compound (132) was prepared according to the proceduresdescribed in Example 102, by using appropriate starting materials. HPLCpurity: 96%; LC-MS m/z: 485 ([M+H]⁺). ¹H NMR (CD₃OD) δ 7.93 (s, 1H),7.88 (d, 1H, J=8.5 Hz), 7.80 (d, 1H, J=8.7 Hz), 7.72 (d, 1H, J=15.8 Hz),6.59 (d, 1H, J=15.8 Hz), 5.00 (t, 2H, J=6.5 Hz), 3.67 (t, 2H, J=7.5 Hz),3.13-3.08 (m, 2H), 1.68-1.64 (m, 4H), 1.14 (s, 9H), 0.96 (s, 18H).

EXAMPLE 105 Preparation of3-{1-[2-(2,2-Dimethyl-propylamino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(133)

The titled compound (133) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 99.9%; LC-MS m/z: 317 ([M+H]⁺). ¹H NMR (CD₃OD) δ8.82 (s, 1H),7.94 (s, 1H), 7.83 (d, 1H, J=8.5 Hz), 7.75 (d, 1H, J=8.7 Hz), 7.66 (d,1H, J=15.8 Hz), 6.53 (d, 1H, J=15.8 Hz), 4.92-4.78 (m, 2H), 3.64 (t, 2H,J=7.0 Hz), 2.98 (s, 2H), 1.09 (s, 9H).

EXAMPLE 106 Preparation of3-(1-{2-[(2,2-Dimethyl-propyl)-propyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(134)

The titled compound (134) was prepared according to the proceduresdescribed in Example 76, by using appropriate starting materials. HPLCpurity: 99.9%; LCMS m/z: 359 ([M+H]⁺). ¹H NMR (CD₃OD) δ 9.07 (s, 1H),7.95 (s, 1H), 7.92 (d, 1H, J=8.7 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.66 (d,1H, J=15.8 Hz), 6.56 (d, 1H, J=15.8 Hz), 4.99-4.97 (m, 2H), 3.74 (t,2H=7.0 Hz), 3.32-3.20 (m, 4H), 1.85-1.82 (m, 2H), 1.03 (s, 9H), 0.92 (t,3H, J=7.1 Hz).

EXAMPLE 107 Preparation of3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(135)

The titled compound (135) was prepared according to the proceduresdescribed in Example 102, by using appropriate starting materials. HPLCpurity: 94.3%; LCMS m/z: 359 ([M+H]⁺). ¹H NMR (CD₃OD) δ 7.69 (d, 1H,J=8.0 Hz), 7.54 (s, 1H), 7.53 (d, 1H, J=109.8 Hz), 6.89 (d, 1H, J=16.1Hz), 6.08 (d, 1H, J=15.7 Hz), 4.80-4.70 (m, 2H), 3.55-3.45 (m, 2H),3.20-3.19 (m, 2H), 2.95-2.90 (m, 2H), 1.56-1.52 (m, 2H), 1.42 (t, 3H,7.4 Hz), 0.81 (s, 9H).

EXAMPLE 108 Preparation of3-[1-(2-Diethylamino-ethyl)-2-propylamino-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(105)

The titled compound (105) was made according to the following syntheticscheme.

HPLC purity: 100%. ¹H-NMR (DMSO-d₆) δ 0.97 (3H, t, J=7.32 Hz), 1.22 (6H,m), 1.68 (2H, m), 3.09-3.60 (10H, m), 6.47 (1H, d, J=15.80 Hz),7.52-7.64 (4H, m), 9.03 (2H, bs), 10.10 (1H, s), 10.81 (1H, s).

EXAMPLE 109 Preparation of3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-propylamino-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide(115)

The titled compound (115) was made by using method analogous to compound(105). HPLC purity: 97%. ¹H-NMR (DMSO-d₆) δ 0.97 (3H, t, J=7.28), 1.15(6H, s), 1.69 (2H, m, J=7.28 Hz), 2.89 (6H, s), 3.28 (2H, s), 3.42 (2H,m), 4.15 (2H, s), 6.47 (2H, d, J=15.80), 7.49-7.75 (4H, m), 8.94 (1H,bs), 9.42 (1H, bs), 10.81 (1H, bs), 13.44 (1H, bs).

EXAMPLE 110 Preparation of3-(1-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-ethyl}-2-propyl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(136)

The titled compound (136) was prepared by reacting of3-{1-[2-(3,3-dimethyl-butylamino)-ethyl]-2-propyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide(130) with formaldehyde (10 eq.) and NaBH₃CN (3 eq.) in MeOH. TFA saltof 136: HPLC purity at 254 nm, 99.8%; LCMS (ESI) m/z: 387 ([M+H]⁺). ¹HNMR (CD₃OD) δ 7.85 (1H, d, J=8.5 Hz), 7.84 (1H, s), 7.74 (1H, d, J=8.3Hz), 7.63 (1H, d, J=15.8 Hz), 6.52 (1H, d, J=15.5 Hz), 4.81 (2H, m),3.62 (2H, br t-like), 3.20 (2H, m), 3.13 (2H, t, J=7.3 Hz), 3.01 (3H,s), 1.93 (2H, m), 1.63 (2H, m), 1.10 (3H, t, J=7.2 Hz), 0.93 (9H, s).

EXAMPLE 111 Preparation of3-(1-{2-[(3,3-Dimethyl-butyl)-(2,2,2-trifluoro-ethyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(137)

The titled compound (137) was prepared as TFA salt according to theprocedures described as below.

Step 1

To a solution of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester(Ia, 3 g, 12 mmol) in dioxane (100 mL) was added 2-aminoethanol (2.2 mL,37 mmol) and triethylamine (3.4 mL, 25 mmol). The reaction mixture washeated at 90° C. for 48 hours where all the starting material has beenconverted to the product. Solvent was evaporated resulting in compound137-1. The solid was washed with water (×3) and dried over Na₂SO₄.Yield: 88%. Purity at 254 nm: 98%, t_(R)=2.4 min. LCMS m/z: 267([M+H]⁺).

Step 2

To a solution of 3-[4-(2-hydroxy-ethylamino)-3-nitro-phenyl]-acrylicacid methyl ester (137-1, 0.200 g, 0.75 mmol) in MeOH (3.7 mL) was addedHCO₂H (0.226 mL, 6 mmol) and SnCl₂.2H₂O (0.982 g, 3.7 mmol). Thereaction mixture was allowed to stir at 50° C. for 16 hours. Solvent wasremoved and the residue was basified and then extracted with ethylacetate. The unpurified crude was used for the next step. LCMS m/z: 247([M+H]⁺).

Step 3

To a solution of crude3-[1-(2-hydroxy-ethyl)-1H-benzoimidazol-5-yl]-acrylic acid methyl ester(137-2, 0.120 g, 0.49 mmol) in CH₂Cl₂ (3.5 mL) was added PPh₃ (0.383 g,1.46 mmol) and CBr₄ (0.485 g, 1.46 mmol). The reaction mixture wasstirred at room temperature for 30 minutes and then washed with water(×2) and brine (×1), dried over Na₂SO₄ and concentrated. Compound 137-3was purified by reverse phase preparative HPLC. Yield: 80%. Purity at254 nm: 99.9%, t_(R)=1.2 min. LCMS m/z: 309/311 ([M+H]⁺).

Step 4

To a solution of 3-[1-(2-bromo-ethyl)-1H-benzoimidazol-5-yl]-acrylicacid methyl ester (137-3, 72 mg, 0.23 mmol) in anhydrousN,N-dimethylformamide (2.5 mL) in a 4 mL vial was added2,2,2-trifluoroethylamine (185 μl, 2.32 mmol) and triethylamine (321 μl,2.32 mmol). The reaction mixture was stirred at 80° C. for 16 hours.Ethyl acetate and water was added to the reaction mixture. The aqueouslayer was extracted with ethyl acetate (×2). Then, the combined organiclayer was washed with water (×1) and brine (×1). The unpurified crudewas used for the next step of reaction. LCMS m/z: 328 ([M+H]⁺).

Step 5

The above crude3-{1-[2-(2,2,2-trifluoroethylamino)ethyl]-1H-benzoimidazol-5-yl}-acrylicacid methyl ester (137-4) was dissolved in MeOH (2 mL) and AcOH (0.5mL). Then, 3,3-dimethylbutyraldehyde (42 μl, 0.336 mmol) was added andthe resulting mixture was stirred for 2 hours prior to the addition ofNaCNBH₃ (21 mg, 0.336 mmol). The reaction mixture was stirred for 30minutes. Solvent was removed and the residue was re-dissolved in CH₂Cl₂and washed with sat. NaHCO₃ (×2), water (×2) and brine (×1). The crude137-5: LCMS m/z: 412 ([M+H]⁺).

Step 6

The crude 137-5 was then converted to the tilted compound (137) as TFAsalt according to the procedures described in Example 1. HPLC purity at254 nm: 99.9%, t_(R)=2.4 min. LCMS m/z: 413 ([M+H]⁺). ¹H NMR (CD₃OD) δ0.79 (9H, s), 1.04-1.08 (2H, m), 2.60-2.64 (2H, m), 3.11 (2H, t, J=5.4Hz), 3.20 (2H, q, J=9.7 Hz), 4.54 (2H, t, J=5.3 Hz), 6.61 (1H, d, J=15.7Hz), 7.74 (1H, d, J=15.7 Hz), 7.85-7.96 (2H, m), 7.99 (1H, s), 9.11 (1H,s).

EXAMPLE 112 Preparation of3-(1-{2-[Butyl-(2,2,2-trifluoro-ethyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide(138)

The titled compound (138) was prepared according to the proceduresdescribed in Example 111, by using appropriate starting materials.

HPLC purity at 254 nm: 99.9%, t_(R)=2.8 min. LCMS m/z: 385 ([M+H]⁺). ¹HNMR (CD₃OD) δ 0.79 (3H, t, J=7.2 Hz), 1.15-1.24 (4H, m), 2.64 (2H, t,J=6.9 Hz), 3.12 (2H, t, J=5.5 Hz), 3.20 (2H, q, J=9.7 Hz), 4.55 (2H, t,J=5.4 Hz), 6.60 (1H, d, J=15.7 Hz), 7.74 (1H, d, J=15.8 Hz), 7.83-7.92(2H, m), 7.98 (1H, s), 9.07 (1H, s).

The following compounds are representative examples prepared by methodsdisclosed or analogous to those disclosed in above Examples 1-112:

Com- m/z pound Structure [M + H]⁺ NAME  1

387 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide  2

359 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-isopropyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide  3

373 3-[2-Butyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide  4

391 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2-methylsulfanyl-ethyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide  5

375 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-ethoxymethyl-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide  6

373 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide  7

359 3-[1-(2-Diethylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide  8

359 3-[2-Butyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide  9

369 3-[2-But-3-ynyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 10

371 3-[2-But-3-enyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide 11

357 3-[2-But-3-enyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 12

355 3-[2-But-3-ynyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 13

413 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide 14

399 3-[1-(2-Diethylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 15

361 3-[1-(2-Diethylamino-ethyl)-2-ethoxymethyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 16

331 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-methyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 17

373 3-[1-(2-Diethylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 18

399 N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]- acrylamide 19

359 3-[2-(2,2-Dimethyl-propyl)-1-(2-isopropylamimo-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 20

401 3-[1-(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 21

387 3-[1-(2-Diisopropylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 22

399 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 23

429 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]- N-hydroxy-acrylamide 24

399 3-[2-Cyclohexyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide 25

409 3-[2-Bicyclo[2.2.1]hept-5-en-2-yl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 26

385 3-[1-(2-Diethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 27

413 3-[1-(2-Diisopropylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 28

371 3-[2-Hex-3-enyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 29

385 3-[2-Hex-3-enyl-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 30

357 3-[1-(2-Ethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 31

387 3-[1-(2-Diethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 32

415 N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]- acrylamide 33

373 3-[2-(2,2-Dimethyl-propyl)-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 34

427 3-[1-(2-Diisopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 35

345 N-Hydroxy-3-[2-isobutyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-acrylamide 36

345 3-[2-(2,2-Dimethyl-propyl)-1-(2-ethylamimo-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 37

331 3-[1-(2-Ethylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 38

443 3-[1-(2-Diisopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide 39

401 N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]- acrylamide 40

387 3-[1-(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 41

415 3-[1-(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 42

345 3-[1-(2-Diethylamino-ethyl)-2-propyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 43

387 3-[2-Butyl-1-(2-diisopropylamimo-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 44

331 3-[2-Butyl-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 45

377 3-[1-(2-Diethylamino-ethyl)-2-(2-methylsulfanyl-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 46

345 3-[2-Butyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 47

359 3-[2-Butyl-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 48

433 3-[1-(1-Benzyl-piperidin-4-yl)-2-butyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 49

329 3-[2-But-3-enyl-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 50

373 3-[2-Hexyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 51

387 3-[1-(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 52

359 3-[1-(2-Ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 53

385 N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]- acrylamide 54

357 3-[1-(2-Dimethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 55

359 3-[1-(2-Amino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 56

403 3-[1-(2-Amino-ethyl)-2-(2-methoxy-nonyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 57

331 3-[2-Butyl-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 58

359 3-[1-(2-Dimethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 59

444 N-{2-[1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2-yl]-ethyl}-3,3-dimethyl-butyramide 60

430 3-{1-(2-Diethylamino-ethyl)-2-[2-(2,2-dimethyl-propionylamino)-ethyl]-1H-benzoimidazol-5-yl}- N-hydroxy-acrylamide 61

416 3-{1-(2-Diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5- yl}-N-hydroxy-acrylamide 62

402 N-[1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2- ylmethyl]-butyramide 63

359 3-[1-(2-ethylamino-ethyl)-2-(3,3-dimethyl-butyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 64

359 3-[2-(3,3-Dimethyl-butyl)-1-(2-Dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 65

345 3-[1-(2-Dimethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 66

357 3-[1-(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 67

396 N-Hydroxy-3-[1-(5-methyl-1H-pyrazol-3-yl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]- acrylamide 68

345 3-[1-(2-Ethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 69

329 3-(2-Butyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide 70

343 3-(2-Butyl-1-piperidin-4-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide 71

359 N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-acrylamide 72

385 N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-non-3-enyl-1H-benzoimidazol-5-yl]-acrylamide 73

385 N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-non-6-enyl-1H-benzoimidazol-5-yl]-acrylamide 74

345 3-[2-Hexyl-1-(2-methylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 75

331 N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-acrylamide 76

373 N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-octyl-1H-benzoimidazol-5-yl]-acrylamide 77

359 3-[1-(2-Amino-ethyl)-2-octyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 78

359 3-{2-Butyl-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 79

359 3-{1-[2-(Ethyl-methyl-amino)-ethyl]-2-pentyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 80

357 3-(2-Hexyl-1-pyrrolidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide 81

343 3-[2-Butyl-1-(1-methyl-pyrrolidin-3-yl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 82

371 3-(2-Hexyl-1-piperidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide 83

343 3-(2-Butyl-1-piperidin-3-yl-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide 84

403 3-(1-{2-[Ethyl-(2-methoxy-ethyl)-amino]-ethyl}-2-pentyl-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide 85

345 3-{2-Butyl-1-[2-(ethyl-methyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 86

371 N-Hydroxy-3-[1-(1-methyl-piperidin-3-yl)-2-pentyl-1H-benzoimidazol-5-yl]-acrylamide 87

359 3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 88

345 3-{1-[2-(Ethyl-pentyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 89

373 3-{1-[2-(Ethyl-heptyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 90

415 3-{2-Hexyl-1-[1-(2-hydroxy-ethyl)-piperidin-3-yl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 91

389 3-(2-Butyl-1-{2-[ethyl-(3-hydroxy-propyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide 92

403 3-(1-{2-[Ethyl-(3-hydroxy-propyl)-amino]-ethyl}-2-pentyl-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide 93

377 (E)-N-hydroxy-3-(1-(1-phenethylpyrrolidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide 94

357 (E)-N-hydroxy-3-(1-(1-pentylpiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide 95

331 3-{1-[2-(Butyl-ethyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 96

391 (E)-N-hydroxy-3-(1-(1-phenethylpiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide 97

405 (E)-N-hydroxy-3-(1-(1-(3-phenylpropyl)piperidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide 98

391 (E)-N-hydroxy-3-(1-(1-(3-phenylpropyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide 99

357 3-{1-[1-(3,3-Dimethyl-butyl)-pyrrolidin-3-yl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 100 

303 (E)-3-(1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide 101 

384 3-[2-(4-Cyano-butyl)-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 102 

343 (E)-3-(1-(1-butylpiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide 103 

355 (E)-N-hydroxy-3-(1-(1-(pent-4-enyl)piperidin-3-yl)-1H-benzo[d]imidazol-5-yl)acrylamide 104 

371 (E)-3-(1-(1-(3,3-dimethylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide 105 

360 3-[1-(2-Diethylamino-ethyl)-2-propylamino-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 107 

331 (E)-N-hydroxy-3-(1-(2- (isopropyl(propyl)amino)ethyl)-1H-benzo[d]imidazol-5-yl)acrylamide 108 

345 3-{1-[2-(Butyl-isopropyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 109 

359 N-Hydroxy-3-{1-[2-(isopropyl-pentyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-acrylamide 110 

398 3-[2-(5-Cyano-pentyl)-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 111 

359 3-(1-{2-[(3,3-Dimethyl-butyl)-ethyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide 112 

317 3-{1-[2-(Ethyl-propyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 113 

373 N-Hydroxy-3-(1-{2-[isopropyl-(2-methyl-pentyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-acrylamide 114 

399 (E)-N-hydroxy-3-(1-(2-(isopropyl(4,4,4-trifluorobutyl)amino)ethyl)-1H-benzo[d]imidazol- 5-yl)acrylamide 115 

374 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-propylamino-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide 116 

373 3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-methyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 117 

399 3-{1-[2-(Butyl-ethyl-amino)-ethyl]-2-trifluoromethyl-1H-benzoimidazol-5-yl}-N- hydroxy-acrylamide 118 

427 3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-trifluoromethyl-1H-benzoimidazol-5-yl}-N- hydroxy-acrylamide 119 

401 (E)-3-(1-(2-(dibutylamino)ethyl)-2-propyl-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide 120 

331 3-[1-(2-Dipropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide 121 

359 N-Hydroxy-3-(1-{2-[isopropyl-(3-methyl-butyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-acrylamide 122 

345 3-(1-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide 123 

345 3-(1-{2-[(2-Ethyl-butyl)-methyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy-acrylamide 124 

415 (E)-3-(1-(2-(bis(3,3-dimethylbutyl)amino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide 125 

359 (E)-3-(1-(2-(diisobutylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide 126 

331 3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 127 

329 N-Hydroxy-3-{1-[2-(methyl-pent-4-enyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-acrylamide 128 

373 3-(1-{2-[(3,3-Dimethyl-butyl)-propyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide 129 

363 3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-methylsulfanyl-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide 130 

373 3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-propyl-1H-benzoimidazol-5-yl}-N-hydroxy- acrylamide 131 

401 3-[1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide 132 

485 3-[1-{2-[Bis-(3,3-dimethyl-butyl)amino]-ethyl}-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide 133 

317 3-{1-[2-(2,2-Dimethyl-propylamino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 134 

359 3-(1-{2-[(2,2-Dimethyl-propyl)-propyl-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide 135 

359 3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide 136 

387 3-(1-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-ethyl}-2-propyl-1H-benzoimidazol-5-yl)-N- hydroxy-acrylamide 137 

413 3-(1-{2-[(3,3-Dimethyl-butyl)-(2,2,2-trifluoro-ethyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N- hydroxy-acrylamide 138 

385 3-(1-{2-[Butyl-(2,2,2-trifluoro-ethyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamideBiological Testing and Enzyme AssaysRecombinant GST-HDAC1 Protein Expression and Purification

Human cDNA library was prepared using cultured SW620 cells.Amplification of human HDAC1 coding region from this cDNA library wascloned separately into the baculovirus expression pDEST20 vector(GATEWAY Cloning Technology, Invitrogen Pte Ltd). The pDEST20-HDAC1construct was confirmed by DNA sequencing. Recombinant baculovirus wasprepared using the Bac-To-Bac method following the manufacturer'sinstruction (Invitrogen Pte Ltd). Baculovirus titer was determined byplaque assay to be about 10⁸ PFU/ml.

Expression of GST-HDAC1 was done by infecting SF9 cells (Invitrogen PteLtd) with pDEST20-HDAC1 baculovirus at MOI=1 for 48 h. Soluble celllysate was incubated with pre-equilibrated Glutathione Sepharose 4Bbeads (Amersham) at 4° C. for 2 h. The beads were washed with PBS bufferfor 3 times. The GST-HDAC1 protein was eluted by elution buffercontaining 50 mM Tris, pH8.0, 150 mM NaCl, 1% Triton X-100 and 10 mM or20 mM reduced Glutathione. The purified GST-HDAC1 protein was dialyzedwith HDAC storage buffer containing 10 mM Tris, pH7.5, 100 mM NaCl and 3mM MgCl₂. 20% Glycerol was added to purified GST-HDAC1 protein beforestorage at −80° C.

In Vitro HDAC Assay for Determination of IC50 Values

The assay has been carried out in 96 well format and the BIOMOLfluorescent-based HDAC activity assay has been applied. The reactioncomposed of assay buffer, containing 25 mM Tris pH 7.5, 137 mM NaCl, 2.7mM KCl, 1 mM MgCl₂, 1 mg/ml BSA, tested compounds, an appropriateconcentration of HDAC1 enzyme, 500 uM Flur de lys generic substrate forHDAC1 enzyme and subsequently was incubated at room temperature for 2 h.Flur de lys Developer was added and the reaction was incubated for 10min. Briefly, deacetylation of the substrate sensitizes it to thedeveloper, which then generates a fluorophore. The fluorophore isexcited with 360 nm light and the emitted light (460 nm) is detected ona fluorometric plate reader (Tecan Ultra Microplate detection system,Tecan Group Ltd.).

The analytical software, Prism 4.0 (GraphPad Software Inc) has been usedto generate IC₅₀ from a series of data. IC₅₀ is defined as theconcentration of compound required for 50% inhibition of HDAC enzymeactivity.

The HDAC enzyme inhibition results of representative compounds are shownin Table 1 (unit is micromolar).

TABLE 1 HDAC1 enzyme activity IC₅₀ (unit is micromolar). Compound IC₅₀(μM) 1 0.042 2 0.38 3 0.15 4 0.12 5 0.17 6 0.18 7 0.091 8 0.052 9 0.2110 0.14 11 0.070 12 0.064 13 0.42 14 0.077 15 0.085 17 0.13 19 0.064 200.26 21 0.38 22 0.064 23 0.045 24 0.51 25 0.23 26 0.040 27 0.23 28 0.02129 0.13 30 0.021 31 0.045 32 0.060 33 0.23 34 0.88 35 0.082 36 0.096 370.091 38 0.56 39 0.024 40 0.027 41 0.062 42 0.15 43 0.33 44 0.054 450.053 46 0.049 47 0.21 48 0.43 49 0.11 50 0.036 51 0.066 52 0.025 530.10 54 0.048 55 0.037 56 0.029 57 0.090 58 0.030 59 0.077 60 0.10 610.070 62 0.054 63 0.051 64 0.10 65 0.078 66 0.34 68 0.034 70 0.068 710.040 72 0.017 73 0.026 74 0.028 75 0.050 76 0.018 77 0.026 78 0.044 790.040 80 0.040 81 0.12 82 0.10 83 0.19 84 0.063 85 0.11 86 0.16 87 0.1088 0.047 89 0.080 90 0.51 91 0.060 92 0.050 93 0.23 94 0.064 95 0.052 960.080 97 0.10 98 0.32 99 0.12 100 0.19 101 0.08 102 0.54 103 0.10 1040.41 105 0.13 107 0.074 108 0.043 109 0.048 110 0.044 111 0.029 112 0.12113 0.016 114 0.063 116 0.10 117 0.19 118 0.48 119 0.18 120 0.11 1210.079 122 0.037 123 0.027 124 0.085 125 0.16 126 0.042 127 0.078 1280.031 129 0.77 130 0.036 131 0.066 133 0.072 134 0.22 135 0.074 1360.053 137 0.093 138 0.10Cell-Based Proliferation Assay for Determination of GI₅₀ Values

Human colon cancer cell lines (Colo205, HCT116), Ovarian cancer cellline (A2780), Hepatoma cell line (HEP3B), Prostate cancer cell line(PC3) were obtained from ATCC or ECACC. Colo205 cells were cultivated inRPMI 1640 containing 2 mM L-Glutamine, 5% FBS, 1.0 mM Na Pyruvate, 1U/ml of penicillin and 1 μg of streptomycin. HCT116 cells werecultivated in McCoy's containing RPMI 1640 containing 2 mM L-Glutamine,5% FBS, 1 U/ml of penicillin and 1 μg of streptomycin. A2780 cells werecultivated in RPMI 1640 containing 2 mM L-Glutamine, 5% FBS, 1 U/ml ofpenicillin and 1 μg of streptomycin. HEP3B cells were cultivated in EMEMcontaining 2 mM L-glutamine, 5% FBS, 1% non essential amino acid, 1 mMNa Pyruvate, 1 U/ml of penicillin and 1 μg of streptomycin. PC3 cellswere cultivated in F12K, 2 mM L-glutamine, 5% FBS, 1 U/ml of penicillinand 1 μg of streptomycin. PC3, Colo205, and HCT116 cells were seeded in96-wells plate at 1000, 5000 and 6000 cells per well respectively. A2780and HEP3B cells were seeded in 96-wells plate at 4000 cells per wellrespectively. The plates were incubated at 37° C., 5% CO₂, for 24 h.Cells were treated with compounds at various concentrations for 96 h.Cell growth was then monitored using CyQUANT® cell proliferation assay(Invitrogen Pte Ltd). Dose response curves were plotted to determineGI₅₀ values for the compounds using XL-fit (ID Business Solution,Emeryville, Calif.). GI₅₀ is defined as the concentration of compoundrequired for 50% inhibition of cell growth.

The cellular or growth inhibition activity results of representativecompounds are shown in Table 2 and 3. The data indicated that thecompounds of this invention are active in the inhibition of tumour cellgrowth.

TABLE 2 Cellular or Growth Inhibition Activity in Colo205 cells (unit ismicromolar) Compound GI₅₀ (μM) 1 0.50 2 2.12 3 2.22 4 2.62 5 2.58 6 2.697 0.81 8 0.56 9 1.87 10 1.77 11 0.48 12 0.51 13 5.5 14 0.63 15 1.50 171.19 19 0.53 20 2.66 21 2.51 22 0.75 23 0.19 24 2.99 25 2.38 26 0.37 271.42 28 0.18 29 1.92 30 0.31 31 0.42 32 0.74 33 2.11 34 4.4 35 0.66 360.86 37 1.09 38 1.94 39 0.23 40 0.16 41 0.92 42 0.98 43 1.86 44 0.87 450.54 46 0.48 47 3.6 48 0.78 49 1.75 50 0.17 51 0.26 52 0.21 53 1.05 540.46 55 0.91 56 0.90 57 0.65 58 0.38 59 2.28 60 2.48 61 1.32 62 2.60 630.54 64 0.73 65 0.56 66 8.8 68 0.52 70 7.0 71 0.24 72 0.16 73 0.23 740.55 75 1.20 76 0.29 77 0.67 78 0.54 79 0.45 80 1.37 81 1.00 82 1.23 834.9 84 1.03 85 1.52 86 2.08 87 1.07 88 0.55 89 0.87 90 8.1 91 2.40 921.82 93 2.14 94 0.60 95 0.57 96 0.70 97 0.67 99 1.89 100 2.25 101 2.44102 2.08 103 0.48 104 1.99 105 1.77 107 0.63 108 0.44 109 0.49 110 1.74111 0.21 112 0.88 113 0.61 114 0.72 116 0.70 117 1.80 118 1.88 119 0.77120 0.49 121 0.49 122 0.15 123 0.15 124 0.54 125 0.68 126 0.42 127 0.34128 0.14 129 3.9 130 0.15 131 0.33 133 0.56 134 2.30 135 0.26 136 0.39137 1.97 138 1.96

TABLE 3 Cellular or Growth Inhibition Activity in Various Cancer CellLines Cell lines Compound HCT116 A2780 PC3 HEP3B 1 ++ +++ +++ ++ 7 + +++ 8 ++ ++ +++ + 22 + +++ +++ 23 ++ +++ +++ 30 ++ +++ +++ 40 +++ +++ +++44 + ++ +++ 46 +++ +++ +++ ++ 50 +++ +++ +++ 52 +++ +++ +++ 58 +++ ++++++ +++ 71 +++ +++ +++ 111 +++ 130 +++ +++ +++ (“+++” for GI₅₀ < 0.5 μM,“++” for GI₅₀ between 0.5 and 1.0 μM, “+” for GI₅₀ between 1.0 μM to 5.0μM)Histone H3 Acetylation Assay

A hallmark of histone deacetylase (HDAC) inhibition is the increase inthe acetylation level of histones. Histone acetylation, including H3, H4and H2A can be detected by immuno-blotting (western-blot). Colo205cells, approximately 5×10⁵ cells, were seeded in the previouslydescribed medium, cultivated for 24 h and subsequently treated with HDACinhibitory agents and a positive control at a final concentration of 10μM. After 24 h, cells were harvested and lysed according to theinstruction from Sigma Mammalian Cell Lysis Kit. The proteinconcentration was quantified using BCA method (Sigma Pte Ltd). Theprotein lysate was separated using 4-12% bis-tris SDS-PAGE gel(Invitrogen Pte Ltd) and was transferred onto PVDF membrane (BioRad PteLtd). The membrane was probed using primary antibody specific foracetylated histone H3 (Upstate Pte Ltd). The detection antibody, goatanti rabbit antibody conjugated with HRP was used according to themanufacturing instruction (Pierce Pte Ltd). After removing the detectionantibody from the membrane, an enhanced chemiluminescent substrate fordetection of HRP (Pierce Pte Ltd) was added onto the membrane. Afterremoving the substrate, the membrane was exposed to an X-ray film(Kodak) for 1 sec-20 mins. The X-ray film was developed using the X-rayfilm processor. The density of each band observed on the developed filmcould be qualitatively analyzed using UVP Bioimaging software (UVP, Inc,Upland, Calif.). The values were then normalized against the density ofactin in the corresponding samples to obtain the expression of theprotein.

The results of immuno-blotting assay using acetylated histone H3antibody are shown in Table 4 for representative compounds of thisinvention.

TABLE 4 Histone Acetylation Compound activities (Histone-3) 1 Active 2Active 3 Active 7 Active 8 Active 11 Active 12 Active 14 Active 17Active 19 Active 22 Active 26 Active 28 Active 30 Active 32 Active 35Active 36 Active 37 Active 39 Active 40 Active 41 Active 42 Active 44Active 45 Active 46 Active 48 Active 49 Active 50 Active 52 Active 55Active 58 Active 63 Active 65 Active 68 Active 71 Active 74 Active 130Active

These data demonstrate that compounds of this invention inhibit histonedeacetylases, thereby resulting in the accumulation of acetylatedhistones such as H3.

Measurement of Microsomal Stability

Metabolic stability measurements in the in vitro using liver microsomesaids in the prediction of the in vivo hepatic clearance and the compoundstability towards phase I biotransformation reactions mediated by P450isozymes.

Pooled human liver microsome (HLM was purchased from BD Gentest (BDBioSciences). The incubations consisted of test compound (5 μM) orcontrol compound (Verapamil), NADPH-generating system solution A (25 mMNADP⁺, 66 mM glucose-6-phosphate, 66 mM MgCl₂ in H₂O), NADPH-generatingsystem solution B (40 U/ml glucose-6-phosphate dehydrogenase in 5 mMsodium citrate) and 1.0 mg/ml microsomal protein, respectively, in 100mM potassium phosphate buffer (pH 7.4). Samples were incubated for 0, 5,15, 30, 45, 60 min. Reaction was terminated with ice-cold 80%acetonitrile and 20% DMSO. Samples were subsequently centrifuged at 4°C. for 15 min at 2,000 rpm. 100 μL of the supernatant was transferred tothe LC-MS Plate for analysis. Before quantitative analysis, the compoundwas tuned in LC/MS machine to get the optimized MS condition. Liquidchromatography was performed on a Luna C18 column (Phenomenex U.S.A,Torrance, Calif.) (2×50 mm, 5 μM). % of the compound remaining (by area)at each time point is calculated with respect to time 0 min. Plot %remaining against time (min) to obtain the curve and use the Prismsoftware to obtain the t_(1/2). These are demonstrated in table 5.

TABLE 5 Compound t_(1/2) (min) 1 >30 2 >30 8 >30 11 >30 12 >30 14 >3019 >30 35 >30 40 >30 44 >30 46 >30 52 >30 58 >30 63 >30 68 >30 71 >3074 >30 78 >30 80 >30 88 >30 108 >30 130 >30

The measured in vitro t_(1/2)>30 mins for the above compounds signifiesthat the contribution towards the clearance of the compound due tometabolism is expected to be low in the in vivo situation and thus helpin yielding longer half-life and increased exposure of the compounds.

The above results demonstrated the compounds of formula (I) weremetabolically stable in human liver microsome assay. Together with theappropriate physicochemical properties, e.g., molecular weight, log Pand high solubility, the above compounds could exhibit adequatepharmacological exposure and effect to the body when administratedintravenously or especially orally.

In Vivo Pharmacokinetic (PK) Studies

Compound was dissolved in appropriate solution (saline or DMA andCremaphor in saline) at 1 mg/ml for intravenous (IV) administration, orin 0.5% methyl cellulose, 0.1% Tween 80 in water at 5 mg/ml for oraladministration. Mice were randomized according to body weight, groupedthree per time point. Mice were administered single IV dose (10 mg/kg)via tail vein, or single oral dose (50 mg/kg) via gavage. At pre-definedtime points (predose, 5 or 10, 30 min, 1, 2, 4, 8, and 24 h), one groupof mice was sacrificed by overdose CO₂ and blood samples were collectedby cardiac puncture. The blood samples were centrifuged immediately for10 min at 3000 rpm to separate plasma, and plasma was kept frozen at−80° C. until analysis by LC/MS/MS. Before sample analysis, the methodwas developed for LC/MS/MS assay. The method was validated forsignal-response of the calibration standards, auto-sampler stability for˜15 hours intra-day and inter-day calibration curve using eightcalibration standards excluding the blank plasma. QC samples at threedifferent concentrations in triplicates were prepared to determine theaccuracy and precision. The extracted QC samples were compared tounextracted samples to determine the extraction efficiency of theanalyte. LLOQ was determined by using triplicate samples of 1 ng/mL and2 ng/mL to obtain accuracy and precision at the low end. Samples wereanalysed using the validated method. Data was analyzed by thenon-compartmental model using WinNolin 4.0 software (Pharsight, MountainView, Calif., USA). The mean values for the plasma compoundconcentration-time profiles were used in mouse PK study.

The PK parameter AUC_(0-last) providing the information on the overallexposure of the drug in vivo is one of the key PK/PD parameters thathelps in predicting the efficacy of an anti-cancer compound. The higherthe AUC value, the better will be the in vivo efficacy of the compoundat similar in vitro potency. Pharmacokinetic data of selected compoundsin Table 5 were shown in Table 6 below.

TABLE 6 Representative pharmacokinetic data [compounds were inhydrochloric acid salt form (2HCl), dosed at 50 mg/kg, p.o.] CompoundAUC_(0-last) (ng · h/ml) 1 1868 8 1836 130 1050

The data in Table 6 further demonstrated that compounds with highmetabolic stability as shown by representative compounds in Table 5together with the appropriate physicochemical properties, e.g.,molecular weight, log P, and high solubility, were able to yieldadequate pharmacological exposure and effect in the animal whenadministrated orally.

In Vivo Antineoplastic (or Anti-Tumor) Effect of HDAC Inhibiting Agents:

The efficacy of the compounds of the invention can then be determinedusing in vivo animal xenograft studies. The animal xenograft model isone of the most commonly used in vivo cancer models.

In these studies Female athymic nude mice (Harlan), 12-14 weeks of agewould be implanted subcutaneously in the flank with 5×10⁶ cells ofHCT116 human colon tumor cells, or with 5×10⁶ cells of A2780 humanovarian tumor cells, or with 5×10⁶ cells of PC3 prostate cancer cells.When the tumor reaches the size 100 mm³, the xenograft nude mice wouldbe paired-match into various treatment groups. The selected HDACinhibitors would be dissolved in appropriate vehicles and administeredto xenograft nude mice intraperitoneally, intravenously or orally dailyfor 14-21 days. The dosing volume will be 0.01 ml/g body weight.Paclitaxol, used as positive control, will be prepared for intravenousadministration in an appropriate vehicle. The dosing volume forPaclitaxol will be 0.01 ml/g body weight. Tumor volume will becalculated every second day or twice-a-week of post injection using theformula: Volume (mm³)=(w²×l)/2, where w=width and l=length in mm of anHCT116, or A2780, or PC3 tumor. Compounds of this invention that aretested would show significant reduction in tumor volume relative tocontrols treated with vehicle only. Acetylated histone relative tovehicle treated control group when measured shall be accumulated. Theresult will therefore indicate that compounds of this invention areefficacious in treating a proliferative disorder/disease such as cancer.

The details of specific embodiments described in this invention are notto be construed as limitations. Various equivalents and modificationsmay be made without departing from the essence and scope of thisinvention, and it is understood that such equivalent embodiments arepart of this invention.

1. A compound of the formula (I):

wherein R¹ is a group of formula:—(CR²⁰R²¹)_(m)—(CR²²R²³)_(n)—(CR²⁴R²⁵)_(o)—NR²⁶R²⁷; R² is selected fromthe group consisting of: alkyl which may be unsubstituted or substitutedwith F, cyano, C₂-C₆alkenyl, or C₂-C₆alkynyl, and heteroalkyl which maybe unsubstituted or substituted by ═O; each R²⁰, R²¹, R²², R²³, R²⁴ andR²⁵ is independently selected from the group consisting of: H andmethyl; each R²⁶ and R²⁷ is independently selected from the groupconsisting of H, hydroxylalkyl and alkyl; m, n and o are integersindependently selected from the group consisting of 0, 1, 2, 3 and 4; ora pharmaceutically acceptable salt or prodrug thereof.
 2. A compoundaccording to claim 1 wherein the sum of m+n+o is an integer selectedfrom the group consisting of 0, 1, 2, 3 and
 4. 3. A compound accordingto claim 2 wherein the sum of m+n+o is 2 or
 3. 4. A compound accordingto claim 3 wherein R¹ is selected from the group consisting of:—(CR²⁰R²¹)₂—NR²⁶R²⁷; —(CR²²R²³)₂—NR²⁶R²⁷; —(CR²⁴R²⁵)₂—NR²⁶R²⁷;—(CR²⁰R²¹)—(CR²²R²³)—NR²⁶R²⁷; —(CR²⁰R²¹)(CR²⁴R²⁵)—NR²⁶R²⁷;—(CR²²R²³)—(CR²⁴R²⁵)—NR²⁶R²⁷; —(CR²⁰R²¹)₃—NR²⁶R²⁷; —(CR²²R²³)₃—NR²⁶R²⁷;—(CR²⁴R²⁵)₃—NR²⁶R²⁷; —(CR²⁰R²¹)₂—(CR²²R²³)—NR²⁶R²⁷;—(CR²⁰R²¹)₂—(CR²⁴R²⁵)—NR²⁶R²⁷; —(CR²⁰R²¹)—(CR²²R²³)₂—NR²⁶R²⁷;—(CR²²R²³)₂—(CR²⁴R²⁵)—NR²⁶R²⁷; —(CR²⁰R²¹)—(CR²⁴R²⁵)₂—NR²⁶R²⁷;—(CR²²R²³)—(CR²⁴R²⁵)₂—NR²⁶R²⁷; and—(CR²⁰R²¹)—(CR²²R²³)—(CR²⁴R²⁵)—NR²⁶R²⁷.
 5. A compound according to claim4 wherein the compound is selected from the group consisting of:


6. A compound according to claim 5 wherein R²⁶ and R²⁷ are independentlyselected from the group consisting of: H and alkyl.
 7. A compoundaccording to claim 6 wherein R²⁶ and R²⁷ are independently selected fromthe group consisting of H, methyl, ethyl, isopropyl, propyl, butyl,isobutyl, pentyl, hexyl and heptyl.
 8. A compound according to claim 1wherein R¹ is a group of formula:


9. A compound according to claim 1 wherein R² is selected from the groupconsisting of ethyl, 1-methyl-ethyl, 2,2,2-trifluoroethyl, propyl,2-methyl-propyl, 2,2-dimethyl-propyl, 3,3,3-trifluoro-propyl, butyl,3,3-dimethyl-butyl, pentyl, 2,4,4-trimethyl-pentyl, hexyl and octyl. 10.The compound of claim 1 wherein the compound is selected from compounds,and their pharmaceutically acceptable salts, selected from the groupconsisting of

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-isopropyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[2-Butyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2-methylsulfanyl-ethyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-ethoxymethyl-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diethylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Butyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-But-3-ynyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[2-But-3-enyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[2-But-3-enyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-But-3-ynyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diethylamino-ethyl)-2-ethoxymethyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-methyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diethylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]- acrylamide

3-[2-(2,2-Dimethyl-propyl)-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]- N-hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Hex-3-enyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Hex-3-enyl-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Ethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

N-Hydroxy-3-[1-(3-isopropylamino-propyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]- acrylamide

3-[2-(2,2-Dimethyl-propyl)-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

N-Hydroxy-3-[2-isobutyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-acrylamide

3-[2-(2,2-Dimethyl-propyl)-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Ethylamino-ethyl)-2-isobutyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diisopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]- acrylamide

3-[1-(2-Ethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Diethylamino-ethyl)-2-propyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Butyl-1-(2-diisopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Butyl-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-(2-methylsulfanyl-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[2-Butyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Butyl-1-(3-isopropylamino-propyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-But-3-enyl-1-(2-ethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Hexyl-1-(2-isopropylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Dimethylamino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-(3,3,3-trifluoro-propyl)-1H-benzoimidaozl-5-yl]- acrylamide

3-[1-(2-Dimethylamino-ethyl)-2-hex-3-enyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Amino-ethyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-Butyl-1-(2-dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Dimethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

N-{2-[1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2-yl]-ethyl}-3,3-dimethyl-butyramide

3-{1-(2-Diethylamino-ethyl)-2-[2-(2,2-dimethyl-propionylamino)-ethyl]-1H-benzoimidazol-5-yl}- N-hydroxy-acrylamide

3-{1-(2-Diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5- yl}-N-hydroxy-acrylamide

N-[1-(2-Diethylamino-ethyl)-5-(2-hydroxycarbamoyl-vinyl)-1H-benzoimidazol-2- ylmethyl]-butyramide

3-[1-(2-ethylamino-ethyl)-2-(3,3-dimethyl-butyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-(3,3-Dimethyl-butyl)-1-(2-Dimethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Dimethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Dimethylamino-ethyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy- acrylamide

3-[1-(2-Ethylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

N-Hydroxy-3-[1-(2-isopropylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-acrylamide

N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-non-3-enyl-1H-benzoimidazol-5-yl]-acrylamide

N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-non-6-enyl-1H-benzoimidazol-5-yl]-acrylamide

3-[2-Hexyl-1-(2-methylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-pentyl-1H-benzoimidazol-5-yl]-acrylamide

N-Hydroxy-3-[1-(2-methylamino-ethyl)-2-octyl-1H-benzoimidazol-5-yl]-acrylamide

3-[1-(2-Amino-ethyl)-2-octyl-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-{2-Butyl-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-{1-[2-(Ethyl-methyl-amino)-ethyl]-2-pentyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-{2-Butyl-1-[2-(ethyl-methyl-amino)-ethyl]-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-(2-Butyl-1-{2-[ethyl-(3-hydroxy-propyl)-amino]-ethyl}-1H-benzoimidazol-5-yl)-N-hydroxy- acrylamide.


11. A pharmaceutical composition including a compound according to claim1 and a pharmaceutically acceptable diluent, excipient or carrier.
 12. Amethod of treating colon cancer in a patient, wherein the methodincludes the administration of a therapeutically effective amount of acompound according to claim 1 to the patient.
 13. A method ofsynthesizing compounds of formula I as defined in claim 1

wherein R¹ and R² are as defined in claim 1, the method including (a)providing a compound of the formula (A1):

wherein L is a leaving group, (b) protecting the carboxyl group toproduce a compound of the formula (A2):

wherein L is a leaving group and P^(c) is a carboxyl protecting group,(c) displacing the leaving group with an amine of formula R¹NH₂ toproduce a compound of the formula:

wherein R¹ is as defined in claim 1 or a protected form thereof, andP^(c) is a carboxyl protecting group (d) optionally reacting thecompound to further functionalise R¹ (e) reducing the nitro group; (f)reacting the reduced product with a compound of formula R²CO₂H or acompound of formula R²CHO and cyclising the product thus produced toproduce a compound of the formula (A4):

wherein R¹ and R² are as defined in claim 1 or protected forms thereof,and P^(c) is a carboxyl protecting group (g) converting the compound toa compound of formula I; wherein (d) can be carried out after any one of(c) (e) or (f) and further wherein (e) and (f) can be carried outsequentially or simultaneously.
 14. A method of synthesizing compoundsof formula I as defined in claim 1

wherein R¹ and R² are as defined in claim 1, the method including: (a)providing an aldehyde of the formula (B1)

wherein R¹ and R² are as defined in claim 1, (b) subjecting the aldehydeto reaction with an appropriately substituted olefination agent toproduce a compound of formula (B2)

wherein R¹ and R² are as defined in claim 1, and P^(c) is H or acarboxyl protecting group (c) converting the compound to a compound offormula I.
 15. A method according to claim 14 wherein (a) includes: (a1)providing a compound of the formula (B3):

wherein L is a leaving group and P^(c) is a carboxyl protecting group,(a2) displacing the leaving group with an amine of formula R to producea compound of the formula (B4):

wherein R¹ is as defined in claim 1 or a protected form thereof, andP^(c) is a carboxyl protecting group (a3) optionally reacting thecompound to further functionalise R¹ (a4) reducing the nitro group; (a5)reacting the reduced product with a compound of formula R²CO₂H or acompound of formula R²CHO and cyclising the product thus produced toproduce a compound of the formula (B5):

wherein R¹ and R² are as defined in claim 1 or protected forms thereof,and P^(c) is a carboxyl protecting group (a6) converting the protectedcarboxyl group to the corresponding aldehyde; wherein (a3) can becarried out after any one of (a2), (a4), (a5) or (a6) and furtherwherein (a4) and (a5) may be carried out sequentially or simultaneously.16. A method of synthesizing compounds of formula I as defined in claim1

wherein R¹ and R², are as defined in claim 1, the method including: (a)providing a compound of the formula (C1)

wherein R¹ and R² are as defined in claim 1 or protected forms thereof,and L¹ is a leaving group (b) converting the compound in (a) to acompound of formula (C2);

wherein R¹ and R² are as defined in claim 1 or protected forms thereof,and P^(c) is H or a carboxyl protecting group (c) converting thecompound to a compound of formula I.
 17. A method according to claim 16wherein (a) includes: (a1) providing a compound of the formula (C3):

wherein L and L¹ are leaving groups, (a2) displacing the leaving group(L) with an amine of formula R¹NH₂ to produce a compound of the formula(C4):

wherein R¹ is as defined in claim 1 or a protected form thereof, and L¹is a leaving group; (a3) optionally reacting the compound to furtherfunctionalise R¹ (a4) reducing the nitro group; (a5) reacting thereduced product with a compound of formula R²CO₂H or a compound offormula R²CHO and cyclising the product thus produced to produce acompound of the formula (C1):

wherein (a3) can be carried out after any one of (a2), (a4) or (a5) andfurther wherein (a4) and (a5) may be carried out sequentially orsimultaneously.
 18. A method according to claim 13 wherein the compoundproduced has the formula:


19. A Compound according to claim 1 selected from the group consistingof:

3-(1-{2-[Ethyl-(3-hydroxy-propyl)-amino]-ethyl}-2-pentyl-1H-benzoimidazol-5-yl)-N- hydroxy-acrylamide

3-[2-(4-Cyano-butyl)-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(2-Diethylamino-ethyl)-2-propylamino-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[2-(5-Cyano-pentyl)-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-propylamino-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-methyl-1H-benzoimidazol-5-yl}-N-hydroxy-acrylamide

3-{1-[2-(Butyl-ethyl-amino)-ethyl]-2-trifluoro-methyl-1H-benzoimidazol-5-yl} -N-hydroxy- acrylamide

3-{1-[2-(Ethyl-hexyl-amino)-ethyl]-2-trifluoro-methyl-1H-benzoimidazol-5-yl}-N-hydroxy- acrylamide

(E)-3-(1-(2-(dibutylamino)ethyl)-2-propyl-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide

3-[1-(3-Dimethylamino-2,2-dimethyl-propyl)-2-methylsulfanyl-1H-benzoimidazol-5-yl]-N- hydroxy-acrylamide

3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-propyl-1H-benzoimidazol-5-yl}-N-hydroxy- acrylamide

3-[1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]- N-hydroxy-acrylamide

3-[1-{2-[Bis-(3,3-dimethyl-butyl)-amino]-ethyl}-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5- yl]-N-hydroxy-acrylamide

3-{1-[2-(3,3-Dimethyl-butylamino)-ethyl]-2-ethyl-1H-benzoimidazol-5-yl}-N-hydroxy- acrylamide

3-(l-{2-[(3,3-Dimethyl-butyl)-methyl-amino]-ethyl}-2-propyl-1H-benzoimidazol-5-yl)-N- hydroxy-acrylamide